Abstract
The Concise Guide to PHARMACOLOGY 2015/16 provides concise overviews of the key properties of over 1750 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.13355/full. G protein‐coupled receptors are one of the eight major pharmacological targets into which the Guide is divided, with the others being: G protein‐coupled receptors, ligand‐gated ion channels, voltage‐gated ion channels, other ion channels, nuclear hormone receptors, catalytic receptors and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The Concise Guide is published in landscape format in order to facilitate comparison of related targets. It is a condensed version of material contemporary to late 2015, which is presented in greater detail and constantly updated on the website www.guidetopharmacology.org, superseding data presented in the previous Guides to Receptors & Channels and the Concise Guide to PHARMACOLOGY 2013/14. It is produced in conjunction with NC‐IUPHAR and provides the official IUPHAR classification and nomenclature for human drug targets, where appropriate. It consolidates information previously curated and displayed separately in IUPHAR‐DB and GRAC and provides a permanent, citable, point‐in‐time record that will survive database updates.
Conflict of interest
The authors state that there are no conflicts of interest to declare.
Overview
The majority of biological solutes are charged organic or inorganic molecules. Cellular membranes are hydrophobic and, therefore, effective barriers to separate them allowing the formation of gradients, which can be exploited, for example, in the generation of energy. Membrane transporters carry solutes across cell membranes, which would otherwise be impermeable to them. The energy required for active transport processes is obtained from ATP turnover or by exploiting ion gradients.
ATP‐driven transporters can be divided into three major classes: P‐type ATPases; F‐type or V‐type ATPases and ATP‐binding cassette transporters. The first of these, P‐type ATPases, are multimeric proteins, which transport (primarily) inorganic cations. The second, F‐type or V‐type ATPases, are proton‐coupled motors, which can function either as transporters or as motors. Last, are ATP‐binding cassette transporters, heavily involved in drug disposition as well as transporting endogenous solutes.
The second largest family of membraine proteins in the human genome, after the G protein‐coupled receptors, are the SLC solute carrier family. Within the solute carrier family, there are not only a great variety of solutes transported, from simple inorganic ions to amino acids and sugars to relatively complex organic molecules like haem. The solute carrier family includes 52 families of almost 400 members. Many of these overlap in terms of the solutes that they carry. For example, amino acids accumulation is mediated by members of the SLC1, SLC3/7, SLC6, SLC15, SLC16, SLC17, SLC32, SLC36, SLC38 and SLC43 families. Further members of the SLC superfamily regulate ion fluxes at the plasma membrane, or solute transport into and out of cellular organelles. Some SLC family members remain orpahn transporters, in as much as a physiological function has yet to be dtermined. Within the SLC superfamily, there is an abundance in diversity of structure. Two families (SLC3 and SLC7) only generate functional transporters as heteromeric partners, where one partner is a single TM domain protein. Membrane topology predictions for other families suggest 3,4,6,7,8,9,10,11,12,13 or 14 TM domains. The SLC transporters include members which function as antiports, where solute movement in one direction is balanced by a solute moving in the reverse direction. Symports allow concentration gradients of one solute to allow movement of a second solute across a membrane. A third, relatively small group are equilibrative transporters, which allow solutes to travel across membranes down their concentration gradients. A more complex family of transporters, the SLC27 fatty acid transporters also express enzymatic function. Many of the transporters also express electrogenic properties of ion channels.
Family structure
This is a complete listing of transporter families included in the online IUPHAR/BPS Guide to PHARMACOLOGY database. Summary information is provided here for a subset of transporters where these are of significant pharmacological interest; further transporters are listed in the database
6113 ATP‐binding cassette transporter family
6113 ABCA subfamily
6115 ABCB subfamily
6116 ABCC subfamily
6117 ABCD subfamily of peroxisomal ABC transporters
6118 ABCG subfamily
6119 F‐type and V‐type ATPases
6119 F‐type ATPase
6120 V‐type ATPase
6120 P‐type ATPases
6121 Na+/K+‐ATPases
6121 Ca2+‐ATPases
6122 H+/K+‐ATPases
6122 Cu+‐ATPases
6122 Phospholipid‐transporting ATPases
6123 Major facilitator superfamily (MFS) of transporters
6123 SLC superfamily of solute carriers
6124 SLC1 family of amino acid transporters
6124 Glutamate transporter subfamily
6126 Alanine/serine/cysteine transporter subfamily
6127 SLC2 family of hexose and sugar alcohol
6127 Class I transporters
6129 Proton‐coupled inositol transporter
6129 SLC3 and SLC7 families of heteromeric amino acid transporters (HATs)
6130 SLC3 family
6130 SLC7 family
6131 SLC4 family of bicarbonate transporters
6132 Anion exchangers
6132 Sodium‐dependent HCO transporters
6133 SLC5 family of sodium‐dependent glucose transporters
6134 Hexose transporter family
6135 Choline transporter
6137 Sodium myo‐inositol cotransporter transporters
6138 SLC6 neurotransmitter transporter family
6138 Monoamine transporter subfamily
6139 GABA transporter subfamily
6141 Glycine transporter subfamily
6142 Neutral amino acid transporter subfamily
6144 SLC8 family of sodium/calcium exchangers
6145 SLC9 family of sodium/hydrogen exchangers
6145 SLC10 family of sodium‐bile acid co‐transporters
6147 SLC11 family of proton‐coupled metal ion transporters
6148 SLC12 family of cation‐coupled chloride transporters
6149 SLC13 family of sodium‐dependent sulphate/carboxylate transporters
6150 SLC14 family of facilitative urea transporters
6151 SLC15 family of peptide transporters
6152 SLC16 family of monocarboxylate transporters
6154 SLC17 phosphate and organic anion transporter
6154 family
6154 Type I sodium‐phosphate co‐transporters
6155 Vesicular glutamate transporters (VGLUTs)
6156 Vesicular nucleotide transporter
6156 SLC18 family of vesicular amine transporters
6158 SLC19 family of vitamin transporters
6159 SLC20 family of sodium‐dependent phosphate transporters
6160 SLC22 family of organic cation and anion transporters
6160 Organic cation transporters (OCT)
6161 Organic zwitterions/cation transporters (OCTN)
6162 Organic anion transporters (OATs)
6163 Urate transporter
– Orphan or poorly characterized SLC22 family members
6163 SLC23 family of ascorbic acid transporters
6164 SLC24 family of sodium/potassium/calcium exchangers
6165 SLC25 family of mitochondrial transporters
6165 Mitochondrial di‐ and tri‐carboxylic acid transporter subfamily
6166 Mitochondrial amino acid transporter subfamily
6167 Mitochondrial phosphate transporters
6167 Mitochondrial nucleotide transporter subfamily
6168 Mitochondrial uncoupling proteins
6169 Miscellaneous SLC25 mitochondrial transporters
6170 SLC26 family of anion exchangers
6170 Selective sulphate transporters
6170 Chloride/bicarbonate exchangers
6171 Anion channels
6171 Other SLC26 anion exchangers
6172 SLC27 family of fatty acid transporters
6173 SLC28 and SLC29 families of nucleoside transporters
6173 SLC28 family
6174 SLC29 family
6176 SLC30 zinc transporter family
6176 SLC31 family of copper transporters
6177 SLC32 vesicular inhibitory amino acid transporter
6178 SLC33 acetylCoA transporter
6179 SLC34 family of sodium phosphate co‐transporters
6180 SLC35 family of nucleotide sugar transporters
6181 SLC36 family of proton‐coupled amino acid transporters
6182 SLC37 family of phosphosugar/phosphate exchangers
6182 SLC38 family of sodium‐dependent neutral amino
6182 acid transporters
6183 System A‐like transporters
6183 System N‐like transporters
6184 Orphan SLC38 transporters
6185 SLC39 family of metal ion transporters
6187 SLC41 family of divalent cation transporters
6187 SLC42 family of Rhesus glycoprotein ammonium transporters
6188 SLC43 family of large neutral amino acid transporters
6189 SLC44 choline transporter‐like family
6190 SLC45 family of putative sugar transporters
6191 SLC46 family of folate transporters
6192 SLC47 family of multidrug and toxin extrusion transporters
6193 SLC49 family of FLVCR‐related heme transporters
6195 SLC51 family of steroid‐derived molecule transporters
ATP‐binding cassette transporter family
Overview
ATP‐binding cassette transporters are ubiquitous membrane proteins characterized by active ATP‐dependent movement of a range of substrates, including ions, lipids, peptides, steroids. Individual subunits are typically made up of two groups of 6TM‐spanning domains, with two nucleotide‐binding domains (NBD). The majority of eukaryotic ABC transporters are ‘full’ transporters incorporating both TM and NBD entities. Some ABCs, notably the ABCD and ABCG families are half‐transporters with only a single membrane spanning domain and one NBD, and are only functional as homo‐ or heterodimers. Eukaryotic ABC transporters convey substrates from the cytoplasm, either out of the cell or into intracellular organelles. Their role in the efflux of exogenous compounds, notably chemotherapeutic agents, has led to considerable interest.
Comments
A further group of ABC transporter‐like proteins have been identified to lack membrane spanning regions and are not believed to be functional transporters, but appear to have a role in protein translation [88, 380]: ABCE1(P61221, also known as OABP or 2'‐5' oligoadenylate‐binding protein); ABCF1(Q8NE71, also known as ABC50 or TNF‐α‐stimulated ABC protein); ABCF2(Q9UG63, also known as iron‐inhibited ABC transporter 2) and ABCF3(Q9NUQ8).
ABCA subfamily
| Nomenclature | ABCA1 | ABCA3 | ABCA4 | ABCA5 |
| Common abreviation | ABC1, CERP | ABC3, ABCC | ABCR | – |
| HGNC, UniProt | ABCA1, O95477 | ABCA3, Q99758 | ABCA4, P78363 | ABCA5, Q8WWZ7 |
| Selective inhibitors | probucol [156, 520] | – | – | – |
| Comments | Loss‐of‐function mutations are associated with Tangier disease, in which plasma HDL cholesterol levels are greatly reduced. ABCA1 is a key player in cholesterol efflux from macrophages to lipid‐free apo‐A1 in a process known as reverse cholesterol transport, a role that is important in atherosclerosis. ABCA1 also controls apoE lipidation, and has a role in Alzheimer's disease, including an impact on amyloid β (APP, P05067) deposition and clearance. ABCA1 is transcriptionally regulated by Liver X Receptors (LXR) and Retinoic X Receptor (RXR), which are being explored as therapeutic targets for development of agonists for treatment of metabolic and neurodegenerative disorders [286]. | Loss‐of‐function mutations are associated with pulmonary surfactant deficiency | Retinal‐specific transporter of N‐retinylPE; loss‐of‐function mutations are associated with childhood‐onset Stargardt disease, a juvenile onset macular degenerative disease. The earlier onset disease is often associated with the more severe and deleterious ABCA4 variants [173]. | |
| ABCA4 facilitates the clearance of all‐trans‐retinal from photoreceptor disc membranes following photoexcitation. ABCA4 can also transport N‐11‐cis‐retinylidene‐phosphatidylethanolamine, the Schiff‐base adduct of 11‐cis‐retinal; loss of function mutation cause a buildup of lipofuscin, atrophy of the central retina, and severe progressive loss in vision [394]. | ABCA5 is a lysosomal protein whose loss of function compromises integrity of lysosomes and leads to intra‐endolysosomal accumulation of cholesterol. It has recently been associated with Congenital Generalized Hypertrichosis Terminalis (CGHT), a hair overgrowth syndrome, in a patient with a mutation in ABCA5 that significantly decreased its expression [113]. |
| Nomenclature | ABCA6 | ABCA7 | ABCA12 |
| HGNC, UniProt | ABCA6, Q8N139 | ABCA7, Q8IZY2 | ABCA12, Q86UK0 |
| Comments | A recent genome wide association study identified an ABCA6 variant associated with cholesterol levels [557]. | Genome wide association studies identify ABCA7 variants as associated with Alzheimer's Disease [232]. | Reported to play a role in skin ceramide formation [555]. A recent study shows that ABCA12 expression also impacts cholesterol efflux from macrophages. ABCA12 is postulated to associate with ABCA1 and LXR beta, and stabilize expression of ABCA1. ABCA12 deficiency causes decreased expression of Abca1, Abcg1 and Nr1h2 [171]. |
Comments
A number of structural analogues are not found in man: Abca14 (ENSMUSG00000062017); Abca15 (ENSMUSG00000054746); Abca16 (ENSMUSG00000051900) and Abca17 (ENSMUSG00000035435).
ABCB subfamily
| Nomenclature | ABCB1 | ABCB2 | ABCB3 | ABCB4 | ABCB5 |
| Common abreviation | MDR1, PGP1 | TAP1 | TAP2 | PGY3 | – |
| HGNC, UniProt | ABCB1, P08183 | TAP1, Q03518 | TAP2, Q03519 | ABCB4, P21439 | ABCB5, Q2M3G0 |
| Comments | Responsible for the cellular export of many therapeutic drugs. The mouse and rat have two Abcb1 genes (gene names; Abcb1a and Abcb1b) while the human has only the one gene, ABCB1. | Endoplasmic reticulum peptide transporter, possibly requires heterodimerdimerization with TAP2. | Endoplasmic reticulum peptide transporter, possibly as requires heterodimerization with TAP1. | Transports phosphatidylcholine from intracellular to extracellular face of the hepatocyte canalicular membrane [375] | Multidrug resistance protein in, and marker of, melanoma cells [433] |
| Nomenclature | ABCB6 | ABCB7 | ABCB8 | ABCB9 | ABCB10 | ABCB11 |
| Common abreviation | MTABC3 | ABC7 | MABC1 | TAPL | MTABC2 | ABC16 |
| HGNC, UniProt | ABCB6, Q9NP58 | ABCB7, O75027 | ABCB8, Q9NUT2 | ABCB9, Q9NP78 | ABCB10, Q9NRK6 | ABCB11, O95342 |
| Comments | Putative mitochondrial porphyrin transporter [290]; other subcellular localizations are possible, such as the plasma membrane, as a specific determinant of the Langereis blood group system [227]. | Mitochondrial; reportedly essential for haematopoiesis [388] | Mitochondrial; suggested to play a role in chemoresistance of melanoma [142] | Reported to be lysosomal [260] | Mitochondrial location; the first human ABC transporter to have a crystal structure reported [448]. | Loss‐of‐function mutations are associated with progressive familial intrahepatic cholestasis type 2 [456] |
ABCC subfamily
| Nomenclature | ABCC1 | ABCC2 | ABCC3 | ABCC4 | ABCC5 | ABCC6 |
| Common abreviation | MRP1 | MRP2, cMOAT | MRP3 | MRP4 | MRP5 | MRP6 |
| HGNC, UniProt | ABCC1, P33527 | ABCC2, Q92887 | ABCC3, O15438 | ABCC4, O15439 | ABCC5, O15440 | ABCC6, O95255 |
| Comments | Exhibits a broad substrate specificity [26], including LTC4 (Km 97 nM [309]) and estradiol‐17β‐glucuronide [460]. | Loss‐of‐function mutations are associated with Dubin‐Johnson syndrome, in which plasma levels of conjugated bilirubin are elevated (OMIM: 237500). | Transports conjugates of glutathione, sulfate or glucuronide [51] | Although reported to facilitate cellular cyclic nucleotide export, this role has been questioned [51]; reported to export prostaglandins in a manner sensitive to NSAIDS [403] | Although reported to facilitate cellular cyclic nucleotide export, this role has been questioned [51] | Loss‐of‐function mutations in ABCC6 are associated with pseudoxanthoma elasticum (OMIM: 264800). |
| Nomenclature | ATP‐binding cassette, sub‐family C(CFTR/MRP), member 8 | ABCC9 | ABCC11 |
| Systematic nomenclature | ABCC8 | – | – |
| Common abreviation | SUR1 | SUR2 | MRP8 |
| HGNC, UniProt | ABCC8, Q09428 | ABCC9, O60706 | ABCC11, Q96J66 |
| Selective inhibitors | repaglinide (pIC50 7) [523] | – | – |
| Comments | The sulfonyurea drugs (acetohexamide, tolbutamide and glibenclamide) appear to bind sulfonylurea receptors and it has been shown experimentally that tritiated glibenclamide can be used to pull out a 140 kDa protein identified as SUR1 (now known as ABCC8) [402]. SUR2 (ABCC9) has also been identified [241]. However, this is not the full mechanism of action and the functional channel has been characterised as a hetero‐octamer formed by four SUR and four Kir6.2 subunits, with the Kir6.2 subunits forming the core ion pore and the SUR subunits providing the regulatory properties [345]. Co‐expression of Kir6.2 with SUR1, reconstitutes the ATP‐dependent K+ conductivity inhibited by the sulfonyureas [241]. | Associated with familial atrial fibrillation, Cantu syndrome and familial isolated dilated cardiomyopathy. | Single nucleotide polymorphisms distinguish wet vs. dry earwax (OMIM: 117800); an association between earwax allele and breast cancer risk is reported in Japanese but not European populations. |
Comments
ABCC7 (also known as CFTR, a 12TM ABC transporter‐type protein, is a cAMP‐regulated epithelial cell membrane Cl‐ channel involved in normal fluid transport across various epithelia and can be viewed in the Chloride channels section of the Guide. ABCC8 (ENSG00000006071, also known as SUR1, sulfonylurea receptor 1) and ABCC9 (ENSG00000069431, also known as SUR2, sulfonylurea receptor 2) are unusual in that they lack transport capacity but regulate the activity of particular K+ channels (Kir6.1‐6.2), conferring nucleotide sensitivity to these channels to generate the canonical KATP channels. ABCC13 (ENSG00000155288) is a possible pseudogene.
ABCD subfamily of peroxisomal ABC transporters
Overview
This family of ‘half‐transporters’ act as homo‐ or heterodimers to accumulate fatty acid‐CoA esters into peroxisomes for oxidative metabolism [273].
| Nomenclature | ABCD1 | ABCD2 | ABCD3 |
| Common abreviation | ALDP | ALDR | PMP70 |
| HGNC, UniProt | ABCD1, P33897 | ABCD2, Q9UBJ2 | ABCD3, P28288 |
| Comments | Transports coenzyme A esters of very long chain fatty acids [558, 559]; loss‐of‐function mutations in ABCD1 are associated with adrenoleukodystrophy (OMIM: 3001002). | Coenzyme A esters of very long chain unsaturated fatty acids [558] | – |
Comments
ABCD4 (ENSG00000119688, also known as PMP69, PXMP1‐L or P70R) appears to be located on the endoplasmic reticulum [271], with an unclear function. Loss‐of‐function mutations in the gene encoding ALDP underlie the metabolic storage disorder X‐linked adrenoleukodystrophy.
Further Reading
Aye IL et al. (2009) Transport of lipids by ABC proteins: interactions and implications for cellular toxicity, viability and function. Chem. Biol. Interact. 180: 327‐39 [PMID:19426719]
Gutmann DA et al. (2010) Understanding polyspecificity of multidrug ABC transporters: closing in on the gaps in ABCB1. Trends Biochem. Sci. 35: 36‐42 [PMID:19819701]
Haenisch S et al. (2014) MicroRNAs and their relevance to ABC transporters. Br J Clin Pharmacol 77: 587‐96 [PMID:24645868]
Hinz A et al. (2012) ABC transporters and immunity: mechanism of self‐defense. Biochemistry 51: 4981‐9 [PMID:22668350]
Kemp S et al. (2011) Mammalian peroxisomal ABC transporters: from endogenous substrates to pathology and clinical significance. Br. J. Pharmacol. 164: 1753‐66 [PMID:21488864]
Kerr ID et al. (2011) The ABCG family of membrane‐associated transporters: you don't have to be big to be mighty. Br. J. Pharmacol. 164: 1767‐79 [PMID:21175590]
López‐Marqués RL et al. (2015) Structure and mechanism of ATP‐dependent phospholipid transporters. Biochim. Biophys. Acta 1850: 461‐475 [PMID:24746984]
Miller DS. (2010) Regulation of P‐glycoprotein and other ABC drug transporters at the blood‐brain barrier. Trends Pharmacol. Sci. 31: 246‐54 [PMID:20417575]
Nishi T et al. (2014) Molecular and physiological functions of sphingosine 1‐phosphate transporters. Biochim. Biophys. Acta 1841: 759‐65 [PMID:23921254]
Phillips MC. (2014) Molecular mechanisms of cellular cholesterol efflux. J. Biol. Chem. 289: 24020‐9 [PMID:25074931]
Procko E et al. (2009) The mechanism of ABC transporters: general lessons from structural and functional studies of an antigenic peptide transporter. FASEB J. 23: 1287‐302 [PMID:19174475]
Ravna AW et al. (2009) Molecular modeling studies of ABC transporters involved in multidrug resistance. Mini Rev Med Chem 9: 186‐93 [PMID:19200023]
Rees DC et al. (2009) ABC transporters: the power to change. Nat. Rev. Mol. Cell Biol. 10: 218‐27 [PMID:19234479]
Seeger MA et al. (2009) Molecular basis of multidrug transport by ABC transporters. Biochim. Biophys. Acta 1794: 725‐37 [PMID:19135557]
Stacy AE et al. (2013) Molecular pharmacology of ABCG2 and its role in chemoresistance. Mol. Pharmacol. 84: 655‐69 [PMID:24021215]
Tarling EJ et al. (2013) Role of ABC transporters in lipid transport and human disease. Trends Endocrinol. Metab. 24: 342‐50 [PMID:23415156]
Westerterp M et al. (2014) ATP‐binding cassette transporters, atherosclerosis, and inflammation. Circ. Res. 114: 157‐70 [PMID:24385509]
Wong K et al. (2014) Towards understanding promiscuity in multidrug efflux pumps. Trends Biochem. Sci. 39: 8‐16 [PMID:24316304]
ABCG subfamily
Overview
This family of ‘half‐transporters’ act as homo‐ or heterodimers; particularly ABCG5 and ABCG8 are thought to be obligate heterodimers. They are associated with cellular export of sterols and phospholipids, as well as exogenous drugs (ABCG2).
| Nomenclature | ABCG1 | ABCG2 | ABCG4 | ABCG5 | ABCG8 |
| Common abreviation | ABC8 | ABCP | – | – | – |
| HGNC, UniProt | ABCG1, P45844 | ABCG2, Q9UNQ0 | ABCG4, Q9H172 | ABCG5, Q9H222 | ABCG8, Q9H221 |
| Comments | Transports sterols and choline phospholipids [275] | Exhibits a broad substrate specificity, including urate and haem, as well as multiple synthetic compounds [275]. The functional transporter is likely to be a homodimer, although higher oligomeric states have also been proposed. | Putative functional dependence on ABCG1 | Transports phytosterols and cholesterol; forms an obligate heterodimer with ABCG8. Loss‐of‐function mutations in ABCG5 are associated with sitosterolemia (OMIM: 210250). | Transports phytosterols and cholesterol; forms an obligate heterodimer with ABCG5. Loss‐of‐function mutations in ABCG8 are associated with sitosterolemia (OMIM: 210250). |
F‐type and V‐type ATPases
Overview
The F‐type (ATP synthase) and the V‐type (vacuolar or vesicular proton pump) ATPases, although having distinct subcellular locations and roles, exhibit marked similarities in subunit structure and mechanism. They are both composed of a ‘soluble’ complex (termed F1 or V1) and a membrane complex (Fo or Vo). Within each ATPase complex, the two individual sectors appear to function as connected opposing rotary motors, coupling catalysis of ATP synthesis or hydrolysis to proton transport. Both the F‐type and V‐type ATPases have been assigned enzyme commission number E.C. 3.6.3.14
F‐type ATPase
Overview
The F‐type ATPase, also known as ATP synthase or ATP phosphohydrolase (H+‐transporting), is a mitochondrial membrane‐associated multimeric complex consisting of two domains, an F0 channel domain in the membrane and an F1 domain extending into the lumen. Proton transport across the inner mitochondrial membrane is used to drive the synthesis of ATP, although it is also possible for the enzyme to function as an ATPase. The ATP5O subunit (oligomycin sensitivity‐conferring protein, OSCP, (P48047)), acts as a connector between F1 and F0 motors.
The F1 motor, responsible for ATP turnover, has the subunit composition α3β3γ δ ε.
The F0 motor, responsible for ion translocation, is complex in mammals, with probably nine subunits centring on A, B, and C subunits in the membrane, together with D, E, F2, F6, G2 and 8 subunits. Multiple pseudogenes for the F0 motor proteins have been defined in the human genome.
V‐type ATPase
Overview
The V‐type ATPase is most prominently associated with lysosomes in mammals, but also appears to be expressed on the plasma membrane and neuronal synaptic vesicles.
The V1 motor, responsible for ATP turnover, has eight subunits with a composition of A‐H.
TheV0 motor, responsible for ion translocation, has six subunits (a‐e).
Further Reading
El Far O et al. (2011) A role for V‐ATPase subunits in synaptic vesicle fusion? J. Neurochem. 117: 603‐12 [PMID:21375531]
Junge W et al. (2009) Torque generation and elastic power transmission in the rotary F(O)F(1)‐ATPase. Nature 459: 364‐70 [PMID:19458712]
Krah A. (2015) Linking structural features from mitochondrial and bacterial F‐type ATP synthases to their distinct mechanisms of ATPase inhibition. Prog. Biophys. Mol. Biol. [PMID:26140992]
Marshansky V et al. (2014) Eukaryotic V‐ATPase: novel structural findings and functional insights. Biochim. Biophys. Acta 1837: 857‐79 [PMID:24508215]
Martínez‐Reyes I et al. (2014) The H(+)‐ATP synthase: a gate to ROS‐mediated cell death or cell survival. Biochim. Biophys. Acta 1837: 1099‐112 [PMID:24685430]
Mindell JA. (2012) Lysosomal acidification mechanisms. Annu. Rev. Physiol. 74: 69‐86 [PMID:22335796]
Nakamoto RK et al. (2008) The rotary mechanism of the ATP synthase. Arch. Biochem. Biophys. 476: 43‐50 [PMID:18515057]
Nakanishi‐Matsui M et al. (2010) The mechanism of rotating proton pumping ATPases. Biochim. Biophys. Acta 1797: 1343‐52 [PMID:20170625]
Okuno D et al. (2011) Rotation and structure of FoF1‐ATP synthase. J. Biochem. 149: 655‐64 [PMID:21524994]
von Ballmoos C et al. (2008) Unique rotary ATP synthase and its biological diversity. Annu Rev Biophys 37: 43‐64 [PMID:18573072]
von Ballmoos C et al. (2009) Essentials for ATP synthesis by F1F0 ATP synthases. Annu. Rev. Biochem. 78: 649‐72 [PMID:19489730]
P‐type ATPases
Overview
Phosphorylation‐type ATPases (EC 3.6.3.‐) are associated with membranes and the transport of ions or phospholipids. Characteristics of the family are the transient phosphorylation of the transporters at an aspartate residue and the interconversion between E1 and E2 conformations in the activity cycle of the transporters, taken to represent ‘half‐channels’ facing the cytoplasm and extracellular/luminal side of the membrane, respectively.
Sequence analysis across multiple species allows the definition of five subfamilies, P1‐P5. The P1 subfamily includes heavy metal pumps, such as the copper ATPases. The P2 subfamily includes calcium, sodium/potassium and proton/potassium pumps. The P4 and P5 subfamilies include putative phospholipid flippases.
Na+/K+‐ATPases
Overview
The cell‐surface Na+/K+‐ATPase is an integral membrane protein which regulates the membrane potential of the cell by maintaining gradients of Na+ and K+ ions across the plasma membrane, also making a small, direct contribution to membrane potential, particularly in cardiac cells. For every molecule of ATP hydrolysed, the Na+/K+‐ATPase extrudes three Na+ ions and imports two K+ ions. The active transporter is a heteromultimer with incompletely defined stoichiometry, possibly as tetramers of heterodimers, each consisting of one of four large, ten TM domain catalytic α subunits and one of three smaller, single TM domain glycoprotein β‐subunits (see table). Additional protein partners known as FXYD proteins (e.g. FXYD2, P54710) appear to associate with and regulate the activity of the pump.
Comments
Na+/K+‐ATPases are inhibited by ouabain and cardiac glycosides, such as digoxin, as well as potentially endogenous cardiotonic steroids [23].
Ca2+‐ATPases
Overview
The sarcoplasmic/endoplasmic reticulum Ca2+‐ATPase (SERCA) is an intracellular membrane‐associated pump for sequestering calcium from the cytosol into intracellular organelles, usually associated with the recovery phase following excitation of muscle and nerves.
The plasma membrane Ca2+‐ATPase (PMCA) is a cell‐surface pump for extruding calcium from the cytosol, usually associated with the recovery phase following excitation of cells. The active pump is a homodimer, each subunit of which is made up of ten TM segments, with cytosolic C‐ and N‐termini and two large intracellular loops.
Secretory pathway Ca2+‐ATPases (SPCA) allow accumulation of calcium and manganese in the Golgi apparatus.
Comments
The fungal toxin ochratoxin A has been described to activate SERCA in kidney microsomes [91]. Cyclopiazonic acid [440], thapsigargin[324] and BHQ are widely employed to block SERCA. Thapsigargin has also been described to block the TRPV1 vanilloid receptor [485].
The stoichiometry of flux through the PMCA differs from SERCA, with the PMCA transporting 1 Ca2+ while SERCA transports 2 Ca2+.
Loss‐of‐function mutations in SPCA1 appear to underlie Hailey‐Hailey disease [234].
H+/K+‐ATPases
Overview
The H+/K+ ATPase is a heterodimeric protein, made up of α and β subunits. The α subunit has 10 TM domains and exhibits catalytic and pore functions, while the β subunit has a single TM domain, which appears to be required for intracellular trafficking and stabilising the α subunit. The ATP4A and ATP4B subunits are expressed together, while the ATP12A subunit is suggested to be expressed with the β1 (ATP1B1) subunit of the Na+/K+‐ATPase [383].
Comments
The gastric H+/K+‐ATPase is inhibited by proton pump inhibitors used for treating excessive gastric acid secretion, including (R)‐lansoprazole and a metabolite of esomeprazole.
Cu+‐ATPases
Overview
Copper‐transporting ATPases convey copper ions across cell‐surface and intracellular membranes. They consist of eight TM domains and associate with multiple copper chaperone proteins (e.g. ATOX1, O00244).
Phospholipid‐transporting ATPases
Overview
These transporters are thought to translocate the aminophospholipids phosphatidylserine and phosphatidylethanolamine from one side of the phospholipid bilayer to the other to generate asymmetric membranes. They are also proposed to be involved in the generation of vesicles from intracellular and cell‐surface membranes.
Comments
Loss‐of‐function mutations in ATP8B1 are associated with type I familial intrahepatic cholestasis.
A further series of structurally‐related proteins have been identified in the human genome, with as yet undefined function, including ATP13A1 (Q9HD20), ATP13A2 (Q9NQ11), ATP13A3 (Q9H7F0), ATP13A4 (Q4VNC1) and ATP13A5(Q4VNC0).
Further Reading
Argüello JM et al. (2012) Metal transport across biomembranes: emerging models for a distinct chemistry. J. Biol. Chem. 287: 13510‐7 [PMID:22389499]
Benarroch EE. (2011) Na+, K+‐ATPase: functions in the nervous system and involvement in neurologic disease. Neurology 76: 287‐93 [PMID:21242497]
Brini M et al. (2009) Calcium pumps in health and disease. Physiol. Rev. 89: 1341‐78 [PMID:19789383]
Bublitz M et al. (2013) Ion pathways in the sarcoplasmic reticulum Ca2+‐ATPase. J. Biol. Chem. 288: 10759‐65 [PMID:23400778]
Bueno‐Orovio A et al. (2014) Na/K pump regulation of cardiac repolarization: insights from a systems biology approach. Pflugers Arch. 466: 183‐93 [PMID:23674099]
Cereijido M et al. (2012) The Na+‐K+‐ATPase as self‐adhesion molecule and hormone receptor. Am. J. Physiol., Cell Physiol. 302: C473‐81 [PMID:22049208]
Contreras‐Ferrat A et al. (2014) Calcium signaling in insulin action on striated muscle. Cell Calcium 56: 390‐6 [PMID:25224502]
Crambert G. (2014) H‐K‐ATPase type 2: relevance for renal physiology and beyond. Am. J. Physiol. Renal Physiol. 306: F693‐700 [PMID:24431203]
Galougahi KK et al. (2012) β‐Adrenergic regulation of the cardiac Na+‐K+ ATPase mediated by oxidative signaling. Trends Cardiovasc. Med. 22: 83‐7 [PMID:23040838]
Gupta SP. (2012) Quantitative structure‐activity relationship studies on Na+,K(+)‐ATPase inhibitors. Chem. Rev. 112: 3171‐92 [PMID:22360614]
Inesi G et al. (2014) Biochemical characterization of P‐type copper ATPases. Biochem. J. 463: 167‐76 [PMID:25242165]
Kaler SG. (2011) ATP7A‐related copper transport diseases‐emerging concepts and future trends. Nat Rev Neurol 7: 15‐29 [PMID:21221114]
Lopez‐Marques RL et al. (2014) P4‐ATPases: lipid flippases in cell membranes. Pflugers Arch. 466: 1227‐40 [PMID:24077738]
Lopreiato R et al. (2014) The plasma membrane calcium pump: new ways to look at an old enzyme. J. Biol. Chem. 289: 10261‐8 [PMID:24570005]
López‐Marqués RL et al. (2011) Pumping lipids with P4‐ATPases. Biol. Chem. 392: 67‐76 [PMID:21194369]
Mattle D et al. (2013) On allosteric modulation of P‐type Cu(+)‐ATPases. J. Mol. Biol. 425: 2299‐308 [PMID:23500486]
Michelangeli F et al. (2011) A diversity of SERCA Ca2+ pump inhibitors. Biochem. Soc. Trans. 39: 789‐97 [PMID:21599650]
Morth JP et al. (2011) A structural overview of the plasma membrane Na+,K+‐ATPase and H+‐ATPase ion pumps. Nat. Rev. Mol. Cell Biol. 12: 60‐70 [PMID:21179061]
Palmgren MG et al. (2011) P‐type ATPases. Annu Rev Biophys 40: 243‐66 [PMID:21351879]
Pittman JK. (2011) Vacuolar Ca(2+) uptake. Cell Calcium 50: 139‐46 [PMID:21310481]
Pizzo P et al. (2011) Ca(2+) signalling in the Golgi apparatus. Cell Calcium 50: 184‐92 [PMID:21316101]
Reinhard L et al. (2013) Na(+),K (+)‐ATPase as a docking station: protein‐protein complexes of the Na(+),K (+)‐ATPase. Cell. Mol. Life Sci. 70: 205‐22 [PMID:22695678]
Sebastian TT et al. (2012) Phospholipid flippases: building asymmetric membranes and transport vesicles. Biochim. Biophys. Acta 1821: 1068‐77 [PMID:22234261]
Sikkel MB et al. (2014) SERCA2a gene therapy in heart failure: an anti‐arrhythmic positive inotrope. Br. J. Pharmacol. 171: 38‐54 [PMID:24138023]
Strehler EE. (2015) Plasma membrane calcium ATPases: From generic Ca(2+) sump pumps to versatile systems for fine‐tuning cellular Ca(2.). Biochem. Biophys. Res. Commun. 460: 26‐33 [PMID:25998731]
Major facilitator superfamily (MFS) of transporters
| Nomenclature | synaptic vesicle glycoprotein 2A |
| HGNC, UniProt | SV2A, Q7L0J3 |
| Inhibitors | levetiracetam (pK i 5.8) [363] – Rat |
SLC superfamily of solute carriers
Overview
The SLC superfamily of solute carriers is the second largest family of membrane proteins after G protein‐coupled receptors, but with a great deal fewer therapeutic drugs that exploit them. As with the ABC transporters, however, they play a major role in drug disposition and so can be hugely influential in determining the clinical efficacy of particular drugs.
48 families are identified on the basis of sequence similarities, but many of them overlap in terms of the solutes that they carry. For example, amino acid accumulation is mediated by members of the SLC1, SLC3/7, SLC6, SLC15, SLC16, SLC17, SLC32, SLC36, SLC38 and SLC43. Further members of the SLC superfamily regulate ion fluxes at the plasma membrane, or solute transport into and out of cellular organelles.
Within the SLC superfamily, there is an abundance in diversity of structure. Two families (SLC3 and SLC7) only generate functional transporters as heteromeric partners, where one partner is a single TM domain protein. Membrane topology predictions for other families suggest 3, 4 6, 7, 8, 9, 10, 11, 12, 13, or 14 TM domains. Functionally, members may be divided into those dependent on gradients of ions (particularly sodium, chloride or protons), exchange of solutes or simple equilibrative gating. For many members, the stoichiometry of transport is not yet established. Furthermore, one family of transporters also possess enzymatic activity (SLC27), while many members function as ion channels (e.g. SLC1A7/EAAT5), which increases the complexity of function of the SLC superfamily.
SLC1 family of amino acid transporters
Overview
The SLC1 family of sodium dependent transporters includes the plasma membrane located glutamate transporters and the neutral amino acid transporters ASCT1 and ASCT2 [7, 32, 264, 265, 378].
Glutamate transporter subfamily
Overview
Glutamate transporters present the unusual structural motif of 8TM segments and 2 re‐entrant loops [208]. The crystal structure of a glutamate transporter homologue (GltPh) from Pyrococcus horikoshii supports this topology and indicates that the transporter assembles as a trimer, where each monomer is a functional unit capable of substrate permeation [53, 406, 533] reviewed by [254]). This structural data is in agreement with the proposed quaternary structure for EAAT2 [185] and several functional studies that propose the monomer is the functional unit [205, 284, 302, 418]. Recent evidence suggests that EAAT3 and EAAT4 may assemble as heterotrimers [362]. The activity of glutamate transporters located upon both neurones (predominantly EAAT3, 4 and 5) and glia (predominantly EAAT 1 and 2) serves, dependent upon their location, to regulate excitatory neurotransmission, maintain low ambient extracellular concentrations of glutamate (protecting against excitotoxicity) and provide glutamate for metabolism including the glutamate‐glutamine cycle. The Na+/K+‐ATPase that maintains the ion gradients that drive transport has been demonstrated to co‐assemble with EAAT1 and EAAT2 [412]. Recent evidence supports altered glutamate transport and novel roles in brain for splice variants of EAAT1 and EAAT2 [184, 303]. Three patients with dicarboxylic aminoaciduria (DA) were recently found to have loss‐of‐function mutations in EAAT3 [24]. DA is characterized by excessive excretion of the acidic amino acids glutamate and aspartate and EAAT3 is the predominant glutamate/aspartate transporter in the kidney. Enhanced expression of EAAT2 resulting from administration of β‐lactam antibiotics (e.g. ceftriaxone) is neuroprotective and occurs through NF‐κB‐mediated EAAT2 promoter activation [181, 306, 414] reviewed by [277]). PPARγ activation (e.g. by rosiglitazone) also leads to enhanced expression of EAAT though promoter activation [411]. In addition, several translational activators of EAAT2 have recently been described [98] along with treatments that increase the surface expression of EAAT2 (e.g. [301, 554]), or prevent its down‐regulation (e.g. [199]). A thermodynamically uncoupled Cl‐ flux, activated by Na+ and glutamate [207, 265, 327] (Na+ and aspartate in the case of GltPh [417]), is sufficiently large, in the instances of EAAT4 and EAAT5, to influence neuronal excitability [476, 498]. Indeed, it has recently been suggested that the primary function of EAAT5 is as a slow anion channel gated by glutamate, rather than a glutamate transporter [176].
Comments
The KB (or Ki) values reported, unless indicated otherwise, are derived from transporter currents mediated by EAATs expressed in voltage‐clamped Xenopus laevis oocytes [141, 443, 444, 492]. KB (or Ki) values derived in uptake assays are generally higher (e.g. [444]). In addition to acting as a poorly transportable inhibitor of EAAT2, (2S,4R)‐4‐methylglutamate, also known as SYM2081, is a competitive substrate for EAAT1 (KM= 54μM; [235, 492]) and additionally is a potent kainate receptor agonist [548] which renders the compound unsuitable for autoradiographic localisation of EAATs [14]. Similarly, at concentrations that inhibit EAAT2, dihydrokainate binds to kainate receptors [444]. WAY‐855 and WAY‐213613 are both non‐substrate inhibitors with a preference for EAAT2 over EAAT3 and EAAT1 [132, 133]. NBI‐59159 is a non‐substrate inhibitor with modest selectivity for EAAT3 over EAAT1 (>10‐fold) and EAAT2 (5‐fold) [99, 130]. Analogously, L‐β‐threo‐benzyl‐aspartate (L‐β‐BA) is a competitive non‐substrate inhibitor that preferentially blocks EAAT3 versus EAAT1, or EAAT2 [150]. [3H](2S,4R)‐4‐methylglutamate demonstrates low affinity binding (KD≅ 6.0 μM) to EAAT1 and EAAT2 in rat brain homogenates [15] and EAAT1 in murine astrocyte membranes [13], whereas [3H]ETB‐TBOA binds with high affinity to all EAATs other than EAAT3 [445]. The novel isoxazole derivative (‐)‐HIP‐A may interact at the same site as TBOA and preferentially inhibit reverse transport of glutamate [97]. Threo‐3‐methylglutamate induces substrate‐like currents at EAAT4, but does not elicit heteroexchange of [3H]‐aspartate in synaptosome preparations, inconsistent with the behaviour of a substrate inhibitor [141]. Parawixin 1, a compound isolated from the venom from the spider Parawixia bistriata is a selective enhancer of the glutamate uptake through EAAT2 but not through EAAT1 or EAAT3 [165, 166]. In addition to the agents listed in the table, DL‐threo‐β‐hydroxyaspartate and L‐trans‐2,4‐pyrolidine dicarboxylate act as non‐selective competitive substrate inhibitors of all EAATs. Zn2+ and arachidonic acid are putative endogenous modulators of EAATs with actions that differ across transporter subtypes (reviewed by [491]).
Alanine/serine/cysteine transporter subfamily
Overview
ASC transporters mediate Na+‐dependent exchange of small neutral amino acids such as Ala, Ser, Cys and Thr and their structure is predicted to be similar to that of the glutamate transporters [16, 489]. ASCT1 and ASCT2 also exhibit thermodynamically uncoupled chloride channel activity associated with substrate transport [63, 541]. Whereas EAATs counter‐transport K+ (see above) ASCTs do not and their function is independent of the intracellular concentration of K+[541].
| Nomenclature | Alanine/serine/cysteine transporter 1 | Alanine/serine/cysteine transporter 2 |
| Systematic nomenclature | SLC1A4 | SLC1A5 |
| Common abreviation | ASCT1 | ASCT2 |
| HGNC, UniProt | SLC1A4, P43007 | SLC1A5, Q15758 |
| Endogenous substrates | L‐cysteine>L‐alanine = L‐serine>L‐threonine | L‐alanine = L‐serine = L‐cysteine (low Vmax) = L‐threonine = L‐glutamine = L‐asparagine≫L‐methionine≅glycine≅L‐leucine>L‐valine>L‐glutamic acid (enhanced at low pH) |
| Stoichiometry | 1 Na+: 1 amino acid (in): 1 Na+: 1 amino acid (out); (homo‐, or hetero‐exchange; [542]) | 1 Na+: 1 amino acid (in): 1 Na+: 1 amino acid (out); (homo‐, or hetero‐exchange; [61]) |
| Inhibitors | – | p‐nitrophenyl glutamyl anilide (pK i 4.3) [151] – Rat, benzylcysteine (pK i 3.1) [206], benzylserine (pK i 3) [206] |
Comments
The substrate specificity of ASCT1 may extend to L‐proline and trans‐4‐hydroxy‐proline[386]. At low pH ( 5.5) both ASCT1 and ASCT2 are able to exchange acidic amino acids such as L‐cysteate and glutamate [466, 489]. In addition to the inhibitors tabulated above, HgCl2, methylmercury and mersalyl, at low micromolar concentrations, non‐competitively inhibit ASCT2 by covalent modificiation of cysteine residues [372].
Further Reading
Bröer S et al. (2011) The role of amino acid transporters in inherited and acquired diseases. Biochem. J. 436: 193‐211 [PMID:21568940]
Chao XD et al. (2010) The role of excitatory amino acid transporters in cerebral ischemia. Neurochem. Res. 35: 1224‐30 [PMID:20440555]
Grewer C et al. (2014) SLC1 glutamate transporters. Pflugers Arch. 466: 3‐24 [PMID:24240778]
Jiang J et al. (2011) New views of glutamate transporter structure and function: advances and challenges. Neuropharmacology 60: 172‐81 [PMID:20708631]
Kanai Y et al. (2013) The SLC1 high‐affinity glutamate and neutral amino acid transporter family. Mol. Aspects Med. 34: 108‐20 [PMID:23506861]
Kim K et al. (2011) Role of excitatory amino acid transporter‐2 (EAAT2) and glutamate in neurodegeneration: opportunities for developing novel therapeutics. J. Cell. Physiol. 226: 2484‐93 [PMID:21792905]
SLC2 family of hexose and sugar alcohol transporters
Overview
The SLC2 family transports D‐glucose, D‐fructose, inositol (e.g. myo‐inositol) and related hexoses. Three classes of glucose transporter can be identified, separating GLUT1‐4 and 14, GLUT6, 8, 10 and 12; and GLUT5, 7, 9 and 11. Modelling suggests a 12 TM membrane topology, with intracellular termini, with functional transporters acting as homodimers or homotetramers.
Class I transporters
Overview
Class I transporters are able to transport D‐glucose, but not D‐fructose, in the direction of the concentration gradient and may be inhibited non‐selectively by phloretin and cytochalasin B. GLUT1 is the major glucose transporter in brain, placenta and erythrocytes, GLUT2 is found in the pancreas, liver and kidneys, GLUT3 is neuronal and placental, while GLUT4 is the insulin‐responsive transporter found in skeletal muscle, heart and adipose tissue. GLUT14 appears to result from gene duplication of GLUT3 and is expressed in the testes [521].
| Nomenclature | Glucose transporter 1 | Glucose transporter 2 | Glucose transporter 3 | Glucose transporter 4 | Glucose transporter 14 |
| Systematic nomenclature | SLC2A1 | SLC2A2 | SLC2A3 | SLC2A4 | SLC2A14 |
| Common abreviation | GLUT1 | GLUT2 | GLUT3 | GLUT4 | GLUT14 |
| HGNC, UniProt | SLC2A1, P11166 | SLC2A2, P11168 | SLC2A3, P11169 | SLC2A4, P14672 | SLC2A14, Q8TDB8 |
| Substrates | D‐glucosamine (D‐glucose = D‐glucosamine) [487], dehydroascorbic acid [39], D‐glucose (D‐glucose = D‐glucosamine) [487] | D‐glucosamine (D‐glucosamine > D‐glucose) [487], D‐glucose (D‐glucosamine > D‐glucose) [487] | D‐glucose | D‐glucosamine (D‐glucosamine ≥ D‐glucose) [487], D‐glucose (D‐glucosamine ≥ D‐glucose) [487] | – |
| Labelled ligands | [3H]2‐deoxyglucose | [3H]2‐deoxyglucose | [3H]2‐deoxyglucose | [3H]2‐deoxyglucose | – |
Class II transporters
Overview
Class II transporters transport D‐fructose and appear to be insensitive to cytochalasin B. Class II transporters appear to be predominantly intracellularly located.
| Nomenclature | Glucose transporter 5 | Glucose transporter 7 | Glucose transporter 9 | Glucose transporter 11 |
| Systematic nomenclature | SLC2A5 | SLC2A7 | SLC2A9 | SLC2A11 |
| Common abreviation | GLUT5 | GLUT7 | GLUT9 | GLUT11 |
| HGNC, UniProt | SLC2A5, P22732 | SLC2A7, Q6PXP3 | SLC2A9, Q9NRM0 | SLC2A11, Q9BYW1 |
| Substrates | D‐fructose (D‐fructose > D‐glucose) [67], D‐glucose (D‐fructose > D‐glucose) [67] | D‐fructose [81], D‐glucose [81] | D‐fructose [75], uric acid [75] | D‐fructose [332], D‐glucose [122] |
| Nomenclature | Glucose transporter 6 | Glucose transporter 8 | Glucose transporter 10 | Glucose transporter 12 |
| Systematic nomenclature | SLC2A6 | SLC2A8 | SLC2A10 | SLC2A12 |
| Common abreviation | GLUT6 | GLUT8 | GLUT10 | GLUT12 |
| HGNC, UniProt | SLC2A6, Q9UGQ3 | SLC2A8, Q9NY64 | SLC2A10, O95528 | SLC2A12, Q8TD20 |
| Substrates | – | D‐glucose [238] | dehydroascorbic acid [308], D‐glucose [308] | D‐glucose [409] |
Proton‐coupled inositol transporter
Overview
Proton‐coupled inositol transporters are expressed predominantly in the brain and can be inhibited by phloretin and cytochalasin B[487].
| Nomenclature | Proton myo‐inositol cotransporter |
| Systematic nomenclature | SLC2A13 |
| Common abreviation | HMIT |
| HGNC, UniProt | SLC2A13, Q96QE2 |
| Substrates | D‐chiro‐inositol [487], myo‐inositol [487], scyllo‐inositol [487], muco‐inositol [487] |
| Stoichiometry | 1 H+ : 1 inositol (in) [118] |
Further Reading
Augustin R. (2010) The protein family of glucose transport facilitators: It's not only about glucose after all. IUBMB Life 62: 315‐33 [PMID:20209635]
Klip A et al. (2014) Signal transduction meets vesicle traffic: the software and hardware of GLUT4 translocation. Am. J. Physiol., Cell Physiol. 306: C879‐86 [PMID:24598362]
Leney SE et al. (2009) The molecular basis of insulin‐stimulated glucose uptake: signalling, trafficking and potential drug targets. J. Endocrinol. 203: 1‐18 [PMID:19389739]
Mueckler M et al. (2013) The SLC2 (GLUT) family of membrane transporters. Mol. Aspects Med. 34: 121‐38 [PMID:23506862]
Uldry M et al. (2004) The SLC2 family of facilitated hexose and polyol transporters. Pflugers Arch. 447: 480‐9 [PMID:12750891]
Wolking S et al. (2014) Focal epilepsy in glucose transporter type 1 (Glut1) defects: case reports and a review of literature. J. Neurol. 261: 1881‐6 [PMID:25022942]
SLC3 and SLC7 families of heteromeric amino acid transporters (HATs)
Overview
The SLC3 and SLC7 families combine to generate functional transporters, where the subunit composition is a disulphide‐linked combination of a heavy chain (SLC3 family) with a light chain (SLC7 family).
SLC3 family
Overview
SLC3 family members are single TM proteins with extensive glycosylation of the exterior C‐terminus, which heterodimerize with SLC7 family members in the endoplasmic reticulum and assist in the plasma membrane localization of the transporter.
SLC7 family
Overview
SLC7 family members may be divided into two major groups: cationic amino acid transporters (CATs) and glycoprotein‐associated amino acid transporters (gpaATs).
Cationic amino acid transporters are 14 TM proteins, which mediate pH‐ and sodium‐independent transport of cationic amino acids (system y+), apparently as an exchange mechanism. These transporters are sensitive to inhibition by N‐ethylmaleimide.
| Nomenclature | High affinity cationic amino acid | Low affinity cationic amino acid | Cationic amino acid | L‐type amino acid transporter 1 |
| transporter 1 | transporter 2 | transporter 3 | ||
| Systematic nomenclature | SLC7A1 | SLC7A2 | SLC7A3 | SLC7A5 |
| Common abreviation | CAT1 | CAT2 | CAT3 | LAT1 |
| HGNC, UniProt | SLC7A1, P30825 | SLC7A2, P52569 | SLC7A3, Q8WY07 | SLC7A5, Q01650 |
| Substrates | L‐ornithine, L‐arginine, L‐lysine, L‐histidine | L‐ornithine, L‐arginine, L‐lysine, L‐histidine | L‐ornithine, L‐arginine, L‐lysine | – |
| Nomenclature | L‐type amino acid transporter 2 | y+L amino acid transporter 1 | y+L amino acid transporter 2 | b0,+‐type amino acid transporter 1 |
| Systematic nomenclature | SLC7A8 | SLC7A7 | SLC7A6 | SLC7A9 |
| Common abreviation | LAT2 | y+LAT1 | y+LAT2 | b0,+AT |
| HGNC, UniProt | SLC7A8, Q9UHI5 | SLC7A7, Q9UM01 | SLC7A6, Q92536 | SLC7A9, P82251 |
| Nomenclature | Asc‐type amino acid transporter 1 | Cystine/glutamate transporter | AGT1 |
| Systematic nomenclature | SLC7A10 | SLC7A11 | SLC7A13 |
| Common abreviation | Asc‐1 | xCT | – |
| HGNC, UniProt | SLC7A10, Q9NS82 | SLC7A11, Q9UPY5 | SLC7A13, Q8TCU3 |
Comments
CAT4 appears to be non‐functional in heterologous expression [516], while SLC7A14 has yet to be characterized.
Glycoprotein‐associated amino acid transporters are 12 TM proteins, which heterodimerize with members of the SLC3 family to act as cell‐surface amino acid exchangers.
Heterodimers between 4F2hc and LAT1 or LAT2 generate sodium‐independent system L transporters. LAT1 transports large neutral amino acids including branched‐chain and aromatic amino acids as well as miglustat, whereas LAT2 transports most of the neutral amino acids.
Heterodimers between 4F2hc and y+LAT1 or y+LAT2 generate transporters similar to the system y+L , which transport cationic (L‐arginine, L‐lysine, L‐ornithine) amino acids independent of sodium and neutral (L‐leucine, L‐isoleucine, L‐methionine, L‐glutamine) amino acids in a partially sodium‐dependent manner. These transporters are N‐ethylmaleimide‐insensitive. Heterodimers between rBAT and b0,+AT appear to mediate sodium‐independent system b0,+ transport of most of the neutral amino acids and cationic amino acids (L‐arginine, L‐lysine and L‐ornithine).
Asc‐1 appears to heterodimerize with 4F2hc to allow the transport of small neutral amino acids (such as L‐alanine, L‐serine, L‐threonine, L‐glutamine and glycine), as well as D‐serine, in a sodium‐independent manner.
xCT generates a heterodimer with 4F2hc for a system x‐ e‐c transporter that mediates the sodium‐independent exchange of L‐cystine and L‐glutamic acid.
AGT has been conjugated with SLC3 members as fusion proteins to generate functional transporters, but the identity of a native heterodimer has yet to be ascertained.
Further Reading
Bhutia YD et al. (2015) Amino Acid transporters in cancer and their relevance to ~glutamine addiction~: novel targets for the design of a new class of anticancer drugs. Cancer Res. 75: 1782‐8 [PMID:25855379]
Closs EI et al. (2006) Structure and function of cationic amino acid transporters (CATs). J. Membr. Biol. 213: 67‐77 [PMID:17417706]
Fotiadis D et al. (2013) The SLC3 and SLC7 families of amino acid transporters. Mol. Aspects Med. 34: 139‐58 [PMID:23506863]
Palacín M et al. (2004) The ancillary proteins of HATs: SLC3 family of amino acid transporters. Pflugers Arch. 447: 490‐4 [PMID:14770309]
Palacín M et al. (2005) The genetics of heteromeric amino acid transporters. Physiology (Bethesda) 20: 112‐24 [PMID:15772300]
Verrey F et al. (2004) CATs and HATs: the SLC7 family of amino acid transporters. Pflugers Arch. 447: 532‐42 [PMID:14770310]
SLC4 family of bicarbonate transporters
Overview
Together with the SLC26 family, the SLC4 family of transporters subserve anion exchange, principally of chloride and bicarbonate (HCO3 ‐), but also carbonate and hydrogen sulphate (HSO4 ‐). SLC4 family members regulate bicarbonate fluxes as part of carbon dioxide movement, chyme neutralization and reabsorption in the kidney.
Within the family, subgroups of transporters are identifiable: the electroneutral sodium‐independent Cl‐/HCO3 ‐ transporters (AE1, AE2 and AE3), the electrogenic sodium‐dependent HCO3 ‐ transporters (NBCe1 and NBCe2) and the electroneutral HCO3 ‐ transporters (NBCn1 and NBCn2). Topographical information derives mainly from study of AE1, abundant in erythrocytes, which suggests a dimeric or tetrameric arrangement, with subunits made up of 13 TM domains and re‐entrant loops at TM9/10 and TM11/12. The N terminus exhibits sites for interaction with multiple proteins, including glycolytic enzymes, haemoglobin and cytoskeletal elements.
Anion exchangers
| Nomenclature | Anion exchange protein 1 | Anion exchange protein 2 | Anion exchange protein 3 | Anion exchange protein 4 |
| Systematic nomenclature | SLC4A1 | SLC4A2 | SLC4A3 | SLC4A9 |
| Common abreviation | AE1 | AE2 | AE3 | AE4 |
| HGNC, UniProt | SLC4A1, P02730 | SLC4A2, P04920 | SLC4A3, P48751 | SLC4A9, Q96Q91 |
| Endogenous substrates | HCO3 ‐, Cl‐ | Cl‐, HCO3 ‐ | Cl‐, HCO3 ‐ | – |
| Stoichiometry | 1 Cl‐ (in) : 1 HCO3 ‐ (out) | 1 Cl‐ (in) : 1 HCO3 ‐ (out) | 1 Cl‐ (in) : 1 HCO3 ‐ (out) | – |
Sodium‐dependent HCO transporters
| Nomenclature | Electrogenic sodium bicarbonate | Electrogenic sodium bicarbonate | Electroneutral sodium bicarbonate |
| cotransporter 1 | cotransporter 4 | cotransporter 1 | |
| Systematic nomenclature | SLC4A4 | SLC4A5 | SLC4A7 |
| Common abreviation | NBCe1 | NBCe2 | NBCn1 |
| HGNC, UniProt | SLC4A4, Q9Y6R1 | SLC4A5, Q9BY07 | SLC4A7, Q9Y6M7 |
| Endogenous substrates | NaHCO3‐ | NaHCO3‐ | NaHCO3‐ |
| Stoichiometry | 1 Na+ : 2/3 HCO3 ‐ (out) or 1 Na+ : CO3 2* | 1 Na+ : 2/3 HCO3 ‐ (out) or 1 Na+ : CO3 2* | 1 Na+ : 1 HCO3 ‐ (out) or 1 Na+ : CO3 2* |
| Nomenclature | Electroneutral sodium bicarbonate | NBCBE | NaBC1 |
| cotransporter 2 | |||
| Systematic nomenclature | SLC4A10 | SLC4A8 | SLC4A11 |
| Common abreviation | NBCn2 | NDCBE | BTR1 |
| HGNC, UniProt | SLC4A10, Q6U841 | SLC4A8, Q2Y0W8 | SLC4A11, Q8NBS3 |
| Endogenous substrates | NaHCO3‐ | NaHCO3‐, Cl‐ | Cl‐, NaHCO3‐ |
| Stoichiometry | 1 Na+ : 1 HCO3 ‐ (out) or 1 Na : CO3 2* | 1 Na+ : 2HCO3 ‐ (in) : 1 Cl‐ (out) | – |
Further Reading
Alper SL. (2009) Molecular physiology and genetics of Na+‐independent SLC4 anion exchangers. J. Exp. Biol. 212: 1672‐83 [PMID:19448077]
Boron WF et al. (2009) Modular structure of sodium‐coupled bicarbonate transporters. J. Exp. Biol. 212: 1697‐706 [PMID:19448079]
Christensen HL et al. (2013) Na(+) dependent acid‐base transporters in the choroid plexus; insights from slc4 and slc9 gene deletion studies. Front Physiol 4: 304 [PMID:24155723]
Kurtz I. (2014) NBCe1 as a model carrier for understanding the structure‐function properties of Na+‐coupled SLC4 transporters in health and disease. Pflugers Arch. 466: 1501‐16 [PMID:24515290]
Liu Y et al. (2012) The physiology of bicarbonate transporters in mammalian reproduction. Biol. Reprod. 86: 99 [PMID:22262691]
Majumdar D et al. (2010) Na‐coupled bicarbonate transporters of the solute carrier 4 family in the nervous system: function, localization, and relevance to neurologic function. Neuroscience 171: 951‐72 [PMID:20884330]
Parker MD et al. (2013) The divergence, actions, roles, and relatives of sodium‐coupled bicarbonate transporters. Physiol. Rev. 93: 803‐959 [PMID:23589833]
Romero MF et al. (2013) The SLC4 family of bicarbonate (HCO_3−) transporters. Mol. Aspects Med. 34: 159‐82 [PMID:23506864]
Ruffin VA et al. (2014) Intracellular pH regulation by acid‐base transporters in mammalian neurons. Front Physiol 5: 43 [PMID:24592239]
Thornell IM et al. (2015) Regulators of Slc4 bicarbonate transporter activity. Front Physiol 6: 166 [PMID:26124722]
SLC5 family of sodium‐dependent glucose transporters
Overview
The SLC5 family of sodium‐dependent glucose transporters includes, in mammals, the Na+/substrate co‐transporters for glucose (e.g. choline), D‐glucose, monocarboxylates, myo‐inositol and I‐[159, 179, 518, 519]. Members of the SLC5 and SLC6 families, along with other unrelated Na+ cotransporters (i.e. Mhp1 and BetP), share a common structural core that contains an inverted repeat of 5TM α‐helical domains [2].
Hexose transporter family
Overview
Detailed characterisation of members of the hexose transporter family is limited to SGLT1, 2 and 3, which are all inhibited in a competitive manner by phlorizin, a natural dihydrocholine glucoside, that exhibits modest selectivity towards SGLT2 (see [518] for an extensive review). SGLT1 is predominantly expressed in the small intestine, mediating the absorption of glucose (e.g. D‐glucose), but also occurs in the brain, heart and in the late proximal straight tubule of the kidney. The expression of SGLT2 is almost exclusively restricted to the early proximal convoluted tubule of the kidney, where it is largely responsible for the renal reabsorption of glucose. SGLT3 is not a transporter but instead acts as a glucosensor generating an inwardly directed flux of Na+ that causes membrane depolarization [120].
Comments
Recognition and transport of substrate by SGLTs requires that the sugar is a pyranose. De‐oxyglucose derivatives have reduced affinity for SGLT1, but the replacement of the sugar equatorial hydroxyl group by fluorine at some positions, excepting C2 and C3, is tolerated (see [518] for a detailed quantification). Although SGLT1 and SGLT2 have been described as high‐ and low‐affinity sodium glucose co‐transporters, respectively, recent work suggests that they have a similar affinity for glucose under physiological conditions [236]. Selective blockers of SGLT2, and thus blocking 50% of renal glucose reabsorption, are in development for the treatment of diabetes (e.g. [80]).
Choline transporter
Overview
The high affinity, hemicholinium‐3‐sensitive, choline transporter (CHT) is expressed mainly in cholinergic neurones on nerve cell terminals and synaptic vesicles (keratinocytes being an additional location). In autonomic neurones, expression of CHT requires an activity‐dependent retrograde signal from postsynaptic neurones [291]. Through recapture of choline generated by the hydrolysis of ACh by acetylcholinesterase, CHT serves to maintain acetylcholine synthesis within the presynaptic terminal [159]. Homozygous mice engineered to lack CHT die within one hour of birth as a result of hypoxia arising from failure of transmission at the neuromuscular junction of the skeletal muscles that support respiration [158]. A low affinity choline uptake mechanism that remains to be identified at the molecular level may involve multiple transporters. In addition, a family of choline transporter‐like (CTL) proteins, (which are members of the SLC44 family) with weak Na+ dependence have been described [477].
| Nomenclature | CHT |
| Systematic nomenclature | SLC5A7 |
| HGNC, UniProt | SLC5A7, Q9GZV3 |
| Substrates | triethylcholine |
| Endogenous substrates | choline |
| Stoichiometry | Na+ : choline (variable stoichimetry); modulated by extracellular Cl‐ [251] |
| Selective inhibitors | hemicholinium‐3 (pK i 7–8) [370] |
| Labelled ligands | [3H]hemicholinium‐3 (pK d 8.2–8.4) |
Comments
Ki and KD values for hemicholinium‐3 listed in the table are for human CHT expressed in Xenopus laevis oocytes [371], or COS‐7 cells [12]. Hemicholinium mustard is a substrate for CHT that causes covalent modification and irreversible inactivation of the transporter. Several exogenous substances (e.g. triethylcholine) that are substrates for CHT act as precursors to cholinergic false transmitters.
Sodium iodide symporter, sodium‐dependent multivitamin transporter and sodium‐coupled monocarboxylate transporters
Overview
The sodium‐iodide symporter (NIS) is an iodide transporter found principally in the thyroid gland where it mediates the accumulation of I‐ within thyrocytes. Transport of I‐ by NIS from the blood across the basolateral membrane followed by apical efflux into the colloidal lumen, mediated at least in part by pendrin (SLC22A4), and most likely not SMCT1 (SLC5A8) as once thought, provides the I‐ required for the synthesis of the thyroid hormones triiodothyronine (triiodothyronine) and thyroxine (T4) [42]. NIS is also expressed in the salivary glands, gastric mucosa, intestinal enterocytes and lactating breast. NIS mediates I‐ absorption in the intestine and I‐ secretion into the milk. SMVT is expressed on the apical membrane of intestinal enterocytes and colonocytes and is the main system responsible for biotin(vitamin H) and pantothenic acid (vitamin B5) uptake in humans [422]. SMVT located in kidney proximal tubule epithelial cells mediates the reabsorption of biotin and pantothenic acid. SMCT1 (SLC5A8), which transports a wide range of monocarboxylates, is expressed in the apical membrane of epithelia of the small intestine, colon, kidney, brain neurones and the retinal pigment epithelium [179]. SMCT2 (SLC5A12) also localises to the apical membrane of kidney, intestine, and colon, but in the brain and retina is restricted to astrocytes and Müller cells, respectively [179]. SMCT1 is a high‐affinity transporter whereas SMCT2 is a low‐affinity transporter. The physiological substrates for SMCT1 and SMCT2 are lactate (L‐lactic acid and D‐lactic acid), pyruvic acid, propanoic acid, and nicotinic acid in non‐colonic tissues such as the kidney. SMCT1 is also likely to be the principal transporter for the absorption of nicotinic acid (vitamin B3) in the intestine and kidney [197]. In the small intestine and colon, the physiological substrates for these transporters are nicotinic acid and the short‐chain fatty acids acetic acid, propanoic acid, and butyric acid that are produced by bacterial fermentation of dietary fiber [350]. In the kidney, SMCT2 is responsible for the bulk absorption of lactate because of its low‐affinity/high‐capacity nature. Absence of both transporters in the kidney leads to massive excretion of lactate in urine and consequently drastic decrease in the circulating levels of lactate in blood [470]. SMCT1 also functions as a tumour suppressor in the colon as well as in various other non‐colonic tissues [180]. The tumour‐suppressive function of SMCT1 is based on its ability to transport pyruvic acid, an inhibitor of histone deacetylases, into cells in non‐colonic tissues [471]; in the colon, the ability of SMCT1 to transport butyric acid and propanoic acid, also inhibitors of histone deacetylases, underlies the tumour‐suppressive function of this transporter [179, 180, 213]. The ability of SMCT1 to promote histone acetylase inhibition through accumulation of butyric acid and propanoic acid in immune cells is also responsible for suppression of dendritic cell development in the colon [451].
| Nomenclature | NIS | SMVT | SMCT1 | SMCT2 |
| Systematic nomenclature | SLC5A5 | SLC5A6 | SLC5A8 | SLC5A12 |
| HGNC, UniProt | SLC5A5, Q92911 | SLC5A6, Q9Y289 | SLC5A8, Q8N695 | SLC5A12, Q1EHB4 |
| Substrates | ClO4‐, SCN‐, I‐, NO3 ‐, pertechnetate | lipoic acid [556], pantothenic acid [556], I‐ [556], biotin [556] | propanoic acid, 3‐bromopyruvate, pyroglutamic acid, nicotinic acid, D‐lactic acid, β‐D‐hydroxybutyric acid, L‐lactic acid, salicylic acid, dichloroacetate, butyric acid, α‐ketoisocaproate, pyruvic acid, acetoacetic acid, benzoate, γ‐hydroxybutyric acid, 2‐oxothiazolidine‐4‐carboxylate, acetic acid, β‐L‐hydroxybutyric acid, 5‐aminosalicylate | pyruvic acid, L‐lactic acid, nicotinic acid |
| Stoichiometry | 2Na+ : 1 I‐ [149]; 1Na+ : 1 ClO4 ‐ [123] | 2Na+ : 1 biotin (or pantothenic acid) [390] | 2Na+ : 1 monocarboxylate [94] | – |
| Inhibitors | – | – | fenoprofen (pIC50 4.6) [248], ibuprofen (pIC50 4.2) [248], ketoprofen (pIC50 3.9) [248] | – |
Comments
I‐, ClO4‐, thiocyanate and NO3 ‐ are competitive substrate inhibitors of NIS [123]. Lipoic acid appears to act as a competitive substrate inhibitor of SMVT [505] and the anticonvulsant drugs primidone and carbamazepine competitively block the transport of biotin by brush border vesicles prepared from human intestine [423].
Sodium myo‐inositol cotransporter transporters
Overview
Three different mammalian myo‐inositol cotransporters are currently known; two are the Na+‐coupled SMIT1 and SMIT2 tabulated below and the third is proton‐coupled HMIT (SLC2A13). SMIT1 and SMIT2 have a widespread and overlapping tissue location but in polarized cells, such as the Madin‐Darby canine kidney cell line, they segregate to the basolateral and apical membranes, respectively [41]. In the nephron, SMIT1 mediates myo‐inositol uptake as a ‘compatible osmolyte’ when inner medullary tubules are exposed to increases in extracellular osmolality, whilst SMIT2 mediates the reabsorption of myo‐inositol from the filtrate. In some species (e.g. rat, but not rabbit) apically located SMIT2 is responsible for the uptake of myo‐inositol from the intestinal lumen [11].
| Nomenclature | SMIT | SGLT6 |
| Systematic nomenclature | SLC5A3 | SLC5A11 |
| Common abreviation | SMIT1 | SMIT2 |
| HGNC, UniProt | SLC5A3, P53794 | SLC5A11, Q8WWX8 |
| Substrates | myo‐inositol, scyllo‐inositol>L‐fucose>L‐xylose>L‐glucose, D‐glucose, α‐MDG>D‐galactose, D‐fucose>D‐xylose [214] | myo‐inositol = D‐chiro‐inositol>D‐glucose>D‐xylose>L‐xylose [95] |
| Stoichiometry | 2 Na+ :1 myo‐inositol [214] | 2 Na+ :1 myo‐inositol [55] |
| Inhibitors | phlorizin [95] | phlorizin (pK i 4.1) [95] |
Comments
The data tabulated are those for dog SMIT1 and rabbit SMIT2. SMIT2 transports D‐chiro‐inositol, but SMIT1 does not. In addition, whereas SMIT1 transports both D‐xylose and L‐xylose and D‐fucose and L‐fucose, SMIT2 transports only the D‐isomers of these sugars [95, 214]. Thus the substrate specificities of SMIT1 (for L‐fucose) and SMIT2 (for D‐chiro‐inositol) allow discrimination between the two SMITs. Human SMIT2 appears not to transport glucose [318].
Further Reading
Bailey CJ. (2011) Renal glucose reabsorption inhibitors to treat diabetes. Trends Pharmacol. Sci. 32: 63‐71 [PMID:21211857]
Chao EC et al. (2010) SGLT2 inhibition–a novel strategy for diabetes treatment. Nat Rev Drug Discov 9: 551‐9 [PMID:20508640]
Darrouzet E et al. (2014) The sodium/iodide symporter: state of the art of its molecular characterization. Biochim. Biophys. Acta 1838: 244‐53 [PMID:23988430]
Haga T. (2014) Molecular properties of the high‐affinity choline transporter CHT1. J. Biochem. 156: 181‐94 [PMID:25073461]
Kinne RK et al. (2011) SGLT inhibitors as new therapeutic tools in the treatment of diabetes. Handb Exp Pharmacol 105‐26 [PMID:21484569]
Whalen K et al. (2015) The Role of Sodium‐Glucose Co‐Transporter 2 Inhibitors in the Treatment of Type 2 Diabetes. Clin Ther 37: 1150‐66 [PMID:25891804]
Wilding JP. (2014) The role of the kidneys in glucose homeostasis in type 2 diabetes: clinical implications and therapeutic significance through sodium glucose co‐transporter 2 inhibitors. Metab. Clin. Exp. 63: 1228‐37 [PMID:25104103]
Wright EM. (2013) Glucose transport families SLC5 and SLC50. Mol. Aspects Med. 34: 183‐96 [PMID:23506865]
Wright EM et al. (2011) Biology of human sodium glucose transporters. Physiol. Rev. 91: 733‐94 [PMID:21527736]
SLC6 neurotransmitter transporter family
Overview
Members of the solute carrier family 6 (SLC6) of sodium‐ and (sometimes chloride‐) dependent neurotransmitter transporters [64, 83, 292] are primarily plasma membrane located and may be divided into four subfamilies that transport monoamines, GABA, glycine and neutral amino acids, plus the related bacterial NSS transporters [424]. The members of this superfamily share a structural motif of 10 TM segments that has been observed in crystal structures of the NSS bacterial homolog LeuTAa, a Na+‐dependent amino acid transporter from Aquiflex aeolicus [527] and in several other transporter families structurally related to LeuT [167].
Monoamine transporter subfamily
Overview
Monoamine neurotransmission is limited by perisynaptic transporters. Presynaptic monoamine transporters allow recycling of synaptically released noradrenaline, dopamine and 5‐hydroxytryptamine.
| Nomenclature | NET | DAT | SERT |
| Systematic nomenclature | SLC6A2 | SLC6A3 | SLC6A4 |
| HGNC, UniProt | SLC6A2, P23975 | SLC6A3, Q01959 | SLC6A4, P31645 |
| Substrates | MPP+, methamphetamine, amphetamine | MPP+, methamphetamine, amphetamine | MDMA, p‐chloroamphetamine |
| Endogenous substrates | dopamine, (‐)‐adrenaline, (‐)‐noradrenaline | dopamine, (‐)‐adrenaline, (‐)‐noradrenaline | 5‐hydroxytryptamine |
| Stoichiometry | 1 noradrenaline: 1 Na+:1 Cl‐ [211] | 1 dopamine: 1‐2 Na+: 1 Cl‐ [210] | 1 5‐HT:1 Na+:1 Cl‐ (in), + 1 K+ (out) [465] |
| Inhibitors | milnacipran (pIC50 9.1) [490], atomoxetine (pK d 8.7) [72], desipramine (pK i 8.7) [368], lofepramine (pK i 8.3) [468], duloxetine (pK i 8.2) [382], nortriptyline (pK i 8.2) [192], amoxapine (pK i 7.9) [21], imipramine (pK i 7.8), doxepin (pK i 7.5) [21], clomipramine (pK d 7.4) [468], levomilnacipran (pIC50 7.4) [499], dosulepin (pK i 7.3) [468], dexamfetamine (pK i 7) [17], amitriptyline (pK i 6.5) [17], nefazodone (pK d 6.4) [72], bupropion (pK i 6.4) [296], trimipramine (pK i 5.6) [468], tapentadol (pK i 5.1) [484] | cocaine (pIC50 7.1) [74] – Rat, dexamfetamine (pK i 7) [17], bupropion (pIC50 6.3) [73], atomoxetine (pK d 6) [72], trimipramine (pK i 5.4) [468], nomifensine | vilazodone (pIC50 8.8–9.3) [108, 226], vortioxetine (pK i 8.8) [30], duloxetine (pK i 8.3) [163], nortriptyline (pK i 8.2) [21], dosulepin (pK i 8.1) [468], atomoxetine (pK d 8.1) [72], desvenlafaxine (pK i 7.8) [128], amoxapine (pK i 7.7) [21], imipramine (pK i 7.7) [462], milnacipran (pIC50 7.3) [490], lofepramine (pK i 7.2) [468], trimipramine (pK i 6.8) [468], desipramine (pK i 6.8) [377], nefazodone (pK d 6.7) [72], levomilnacipran (pIC50 6.5) [499] |
| (Sub)family‐selective inhibitors | desvenlafaxine (pK i<6.2) [128], sibutramine (pK i 5.2) [21] | sibutramine (pK i 6.3) [21] | sibutramine (pK i 6) [21] |
| Selective inhibitors | mazindol (pK i 8.9), protriptyline (pIC50 8.8) [352], nisoxetine (pK i 8.4), protriptyline (pK i 8.2) [320], nomifensine (pK i 8.1), reboxetine (pK i 8) [517], maprotiline (pK i 7.9) [225], methylphenidate (pIC50 7.2) | mazindol (pK i 8), WIN35428 (pK i 7.9) [404], GBR12935 (pK i 7.6), dexmethylphenidate (pK i 7.6) [297], methylphenidate (pIC50 7.1) [170] | clomipramine (pK i 9.7) [468], paroxetine (pK i 9.6) [468], clomipramine (pK d 9.6) [468], sertraline (pK i 9.1), escitalopram (pIC50 9) [413], dapoxetine (pIC50 8.9) [186], fluvoxamine (pK d 8.7) [468], fluoxetine (pK i 8.5) [468], citalopram (pK i 8.4) [34], protriptyline (pK d 7.7) [468], venlafaxine (pIC50 7.6) [419], amitriptyline (pK i 6.8) [17] |
| Labelled ligands | [3H]mazindol (Inhibitor) (pK d 9.3) [396] – Rat, [3H]nisoxetine (Inhibitor) (pK d 8.4) | [3H]GBR12935 (Inhibitor) (pK d 8.5) [391], [3H]WIN35428 (Inhibitor) (pK d 8) [391] | [3H]paroxetine (Inhibitor) (pK d 9.7), [3H]citalopram (Inhibitor) (pK d 8.3) |
Comments
[125I]RTI55 labels all three monoamine transporters (NET, DAT and SERT) with affinities between 0.5 and 5 nM. Cocaine is an inhibitor of all three transporters with pKi values between 6.5 and 7.2. Potential alternative splicing sites in non‐coding regions of SERT and NET have been identified. A bacterial homologue of SERT shows allosteric modulation by selected anti‐depressants [452].
GABA transporter subfamily
Overview
The activity of GABA‐transporters located predominantly upon neurones (GAT‐1), glia (GAT‐3) or both (GAT‐2, BGT‐1) serves to terminate phasic GABA‐ergic transmission, maintain low ambient extracellular concentrations of GABA, and recycle GABA for reuse by neurones. Nonetheless, ambient concentrations of GABA are sufficient to sustain tonic inhibition mediated by high affinity GABAA receptors in certain neuronal populations [442]. GAT1 is the predominant GABA transporter in the brain and occurs primarily upon the terminals of presynaptic neurones and to a much lesser extent upon distal astocytic processes that are in proximity to axons terminals. GAT3 resides predominantly on distal astrocytic terminals that are close to the GABAergic synapse. By contrast, BGT1 occupies an extrasynaptic location possibly along with GAT2 which has limited expression in the brain [329]. TauT is a high affinity taurine transporter involved in osmotic balance that occurs in the brain and non‐neuronal tissues, such as the kidney, brush border membrane of the intestine and blood brain barrier [83, 219]. CT1, which transports creatine, has a ubiquitous expression pattern, often co‐localizing with creatine kinase [83].
| Nomenclature | GAT1 | GAT2 | GAT3 |
| Systematic nomenclature | SLC6A1 | SLC6A13 | SLC6A11 |
| HGNC, UniProt | SLC6A1, P30531 | SLC6A13, Q9NSD5 | SLC6A11, P48066 |
| Substrates | nipecotic acid, guvacine | nipecotic acid, guvacine | guvacine, nipecotic acid |
| Endogenous substrates | GABA | β‐alanine, GABA | β‐alanine, GABA |
| Stoichiometry | 2Na+: 1Cl‐: 1GABA | 2Na+: 1Cl‐:1GABA | ≥ 2Na+: 2 Cl‐: 1GABA |
| Selective inhibitors | NNC‐711 (pIC50 7.4) [50], tiagabine (pIC50 7.2) [50], SKF89976A (pIC50 6.9) [117], CI‐966 (pIC50 6.6) [50], (R/S) EF‐1500 (pIC50 4.9–5.7), (R)‐EF‐1520 (pIC50 5.1–5.4), LU32‐176B (pIC50 5.4) [512] – Mouse, (S)‐EF‐1520 (pIC50 3.6–3.9) | SNAP‐5114 (pIC50 4.7) [49] – Rat | – |
| Labelled ligands | [3H]tiagabine (Inhibitor) | – | – |
| Nomenclature | BGT1 | TauT | CT1 |
| Systematic nomenclature | SLC6A12 | SLC6A6 | SLC6A8 |
| HGNC, UniProt | SLC6A12, P48065 | SLC6A6, P31641 | SLC6A8, P48029 |
| Endogenous substrates | GABA, betaine | β‐alanine, taurine, GABA [9] | creatine |
| Stoichiometry | 3Na+: 1 (or 2) Cl‐: 1GABA | 2Na+: 1Cl‐: 1 taurine | Probably 2Na+: 1Cl‐: 1 creatine |
| Selective inhibitors | NNC052090 (pK i 5.9) [473] – Mouse, (R/S) EF‐1500 (pIC50 4.9), (R)‐EF‐1520 (pIC50 3.7–4.7), (S)‐EF‐1520 (pIC50 3.6–4.5), LU32‐176B (pIC50 4) [512] – Mouse | – | – |
Comments
The IC50 values for GAT1‐4 reported in the table reflect the range reported in the literature from studies of both human and mouse transporters. There is a tendency towards lower IC50 values for the human orthologue [295]. SNAP‐5114 is only weakly selective for GAT 2 and GAT3, with IC50 values in the range 22 to >30 μM at GAT1 and BGT1, whereas NNC052090 has at least an order of magnitude selectivity for BGT1 [see [93, 438] for reviews]. Compound (R)‐4d [PMID: 16766089] is a recently described compound that displays 20‐fold selectivity for GAT3 over GAT1 [174]. In addition to the inhibitors listed, deramciclane is a moderately potent, though non‐selective, inhibitor of all cloned GABA transporters (IC50 = 26‐46 μM; [116]). Diaryloxime and diarylvinyl ether derivatives of nipecotic acid and guvacine that potently inhibit the uptake of [3H]GABA into rat synaptosomes have been described [282]. Several derivatives of exo‐THPO(e.g. N‐methyl‐exo‐THPO and N‐acetyloxyethyl‐exo‐THPO) demonstrate selectivity as blockers of astroglial, versus neuronal, uptake of GABA[see [93, 437] for reviews]. GAT3 is inhibited by physiologically relevant concentrations of Zn2+[96]. Taut transports GABA, but with low affinity, but CT1 does not, although it can be engineered to do so by mutagenesis guided by LeuT as a structural template [121]. Although inhibitors of creatine transport by CT1 (e.g. β‐guanidinopropionic acid, cyclocreatine, guanidinoethane sulfonic acid) are known (e.g. [103]) they insufficiently characterized to be included in the table.
Glycine transporter subfamily
Overview
Two gene products, GlyT1 and GlyT2, are known that give rise to transporters that are predominantly located on glia and neurones, respectively. Five variants of GlyT1 (a,b,c,d & e) differing in their N‐ and C‐termini are generated by alternative promoter usage and splicing, and three splice variants of GlyT2 (a,b & c) have also been identified (see [36, 152, 194, 459] for reviews). GlyT1 transporter isoforms expressed in glia surrounding glutamatergic synapses regulate synaptic glycine concentrations influencing NMDA receptor‐mediated neurotransmission [35, 175], but also are important, in early neonatal life, for regulating glycine concentrations at inhibitory glycinergic synapses [195]. Homozygous mice engineered to totally lack GlyT1 exhibit severe respiratory and motor deficiencies due to hyperactive glycinergic signalling and die within the first postnatal day [195, 479]. Disruption of GlyT1 restricted to forebrain neurones is associated with enhancement of EPSCs mediated by NMDA receptors and behaviours that are suggestive of a promnesic action [532]. GlyT2 transporters localised on the axons and boutons of glycinergic neurones appear crucial for efficient transmitter loading of synaptic vesicles but may not be essential for the termination of inhibitory neurotransmission [196, 415]. Mice in which GlyT2 has been deleted develop a fatal hyperekplexia phenotype during the second postnatal week [196] and mutations in the human gene encoding GlyT2 (SLC6A5) have been identified in patients with hyperekplexia (reviewed by [221]). ATB0+(SLCA14) is a transporter for numerous dipolar and cationic amino acids and thus has a much broader substrate specificity than the glycine transporters alongside which it is grouped on the basis of structural similarity [83]. ATB0+ is expressed in various peripheral tissues [83]. By contrast PROT (SLC6A7), which is expressed only in brain in association with a subset of excitatory nerve terminals, shows specificity for the transport of L‐proline.
| Nomenclature | GlyT1 | GlyT2 | ATB0,+ | PROT |
| Systematic nomenclature | SLC6A9 | SLC6A5 | SLC6A14 | SLC6A7 |
| HGNC, UniProt | SLC6A9, P48067 | SLC6A5, Q9Y345 | SLC6A14, Q9UN76 | SLC6A7, Q99884 |
| Endogenous substrates | – | – | L‐isoleucine>L‐leucine, L‐methionine>L‐phenylalanine>L‐tryptophan>L‐valine>L‐serine [453] | – |
| Substrates | – | – | BCH, zwitterionic or cationic NOS inhibitors [224], 1‐methyltryptophan [270], valganciclovir [488] | – |
| Endogenous substrates | sarcosine, glycine | glycine | β‐alanine [8, 9] | L‐proline |
| Stoichiometry | 2 Na+: 1 Cl‐: 1 glycine | 3 Na+: 1 Cl‐: 1 glycine | 2‐3 Na+: 1 Cl‐: 1 amino acid [453] | Probably 2 Na+: 1 Cl‐: 1 L‐proline |
| Inhibitors | – | bitopertin (pEC50<4.5) [385] | – | – |
| Selective inhibitors | (R)‐NFPS (pIC50 8.5–9.1), SSR‐103800 (pIC50 8.7) [54], N‐methyl‐SSR504734 (pIC50 8.6), LY2365109 (pIC50 7.8), GSK931145 (pIC50 7.6), bitopertin (pEC50 7.5) [385] | Org 25543 (pIC50 7.8) [76], ALX 1393, ALX 1405 | α‐methyl‐D,L‐tryptophan (pIC50 3.6) [270] | compound 58 [PMID: 25037917] (pIC50 7.7) [553], LP‐403812 (pIC50 7) [535] |
| Labelled ligands | [3H](R)‐NPTS (Binding) (pK d 9) [323], [3H]GSK931145 (Binding) (pK d 8.8) [229], [35S]ACPPB (Binding) (pK d 8.7) [540], [3H]SB‐733993 (Binding) (pK d 8.7) [229], [3H]N‐methyl‐SSR504734 (pK d 8.1–8.5), [3H]NFPS (pK d 7.7–8.2) | – | – | – |
| Comments | – | N‐Oleoyl‐L‐carnitine (0.3μM, [71]) and and N‐arachidonoylglycine (IC50 5‐8 μM, [513]) have been described as potential endogenous selective GlyT2 inhibitors | – | – |
Comments
sarcosine is a selective transportable inhibitor of GlyT1 and also a weak agonist at the glycine binding site of the NMDA receptor [544], but has no effect on GlyT2. This difference has been attributed to a single glycine residue in TM6 (serine residue in GlyT2) [493]. Inhibition of GLYT1 by the sarcosine derivatives NFPS, NPTS and Org 24598 is non‐competitive [331, 341]. IC50 values for Org 24598 reported in the literature vary, most likely due to differences in assay conditions [58, 331]. The tricyclic antidepressant amoxapine weakly inhibits GlyT2 (IC50 92 μM) with approximately 10‐fold selectivity over GlyT1 [366]. The endogenous lipids arachidonic acid and anandamide exert opposing effects upon GlyT1a, inhibiting (IC50 2 μM) and potentiating (EC50 13 μM) transport currents, respectively [381]. N‐arachidonyl‐glycine, N‐arachidonyl‐γ‐aminobutyric acid and N‐arachidonyl‐D‐alanine have been described as endogenous non‐competitive inhibitors of GlyT2a, but not GlyT1b [136, 253, 513]. Protons [20] and Zn2+[257] act as non‐competitive inhibitors of GlyT1b, with IC50 values of 100 nM and 10 μM respectively, but neither ion affects GlyT2 (reviewed by [491]). Glycine transport by GLYT1 is inhibited by Li+, whereas GLYT2 transport is stimulated (both in the presence of Na+) [392].
Neutral amino acid transporter subfamily
Overview
Certain members of neutral amino acid transport family are expressed upon the apical surface of epithelial cells and are important for the absorption of amino acids from the duodenum, jejunum and ileum and their reabsorption within the proximal tubule of the nephron (i.e. B0AT1 (SLC6A19), SLC6A17, SLC6A18, SLC6A20). Others may function as transporters for neurotransmitters or their precursors (i.e. B0AT2, SLC6A17) [65].
| Nomenclature | B0AT1 | B0AT2 | B0AT3 |
| Systematic nomenclature | SLC6A19 | SLC6A15 | SLC6A18 |
| HGNC, UniProt | SLC6A19, Q695T7 | SLC6A15, Q9H2J7 | SLC6A18, Q96N87 |
| Endogenous substrates | L‐leucine, L‐methionine, L‐isoleucine, L‐valine>L‐asparagine, L‐phenylalanine, L‐alanine, L‐serine>L‐threonine, glycine, L‐proline [64] | L‐proline>L‐alanine, L‐valine, L‐methionine, L‐leucine>L‐isoleucine, L‐threonine, L‐asparagine, L‐serine, L‐phenylalanine>glycine [64] | L‐alanine, glycine>L‐methionine, L‐phenylalanine, L‐leucine, L‐histidine, L‐glutamine [494] |
| Stoichiometry | 1 Na+: 1 amino acid [70] | 1 Na+: 1 amino acid [62] | Na+‐ and Cl‐ ‐dependent transport [450] |
| Inhibitors | nimesulide (pIC50 4.6) [387] – Rat | – | – |
| Selective inhibitors | – | loratadine (pIC50 5.4) [102] | – |
| Comments | Mutations in B0AT1 are associated with Hartnup disorder | – | – |
| Nomenclature | NTT5 | NTT4 | SIT1 |
| Systematic nomenclature | SLC6A16 | SLC6A17 | SLC6A20 |
| HGNC, UniProt | SLC6A16, Q9GZN6 | SLC6A17, Q9H1V8 | SLC6A20, Q9NP91 |
| Endogenous substrates | – | L‐leucine, L‐methionine, L‐proline>L‐cysteine, L‐alanine, L‐glutamine, L‐serine>L‐histidine, glycine [537] | – |
| Endogenous substrates | – | – | L‐proline |
| Stoichiometry | – | Na+‐dependent, Cl‐‐independent transport [537] | 2 Na+: 1 Cl‐: 1 imino acid [60] |
Further Reading
Bröer S et al. (2012) The solute carrier 6 family of transporters. Br. J. Pharmacol. 167: 256‐78 [PMID:22519513]
Chiba P et al. (2014) Defining the blanks–pharmacochaperoning of SLC6 transporters and ABC transporters. Pharmacol. Res. 83: 63‐73 [PMID:24316454]
Harvey RJ et al. (2013) Glycine transporters as novel therapeutic targets in schizophrenia, alcohol dependence and pain. Nat Rev Drug Discov 12: 866‐85 [PMID:24172334]
Kempson SA et al. (2014) The betaine/GABA transporter and betaine: roles in brain, kidney, and liver. Front Physiol 5: 159 [PMID:24795654]
Penmatsa A et al. (2013) X‐ray structure of dopamine transporter elucidates antidepressant mechanism. Nature 503: 85‐90 [PMID:24037379]
Pramod AB et al. (2013) SLC6 transporters: structure, function, regulation, disease association and therapeutics. Mol. Aspects Med. 34: 197‐219 [PMID:23506866]
Ramamoorthy S et al. (2011) Regulation of monoamine transporters: Role of transporter phosphorylation. Pharmacol. Ther. 129: 220‐38 [PMID:20951731]
Reynolds GP et al. (2014) Pharmacogenomics in psychiatry: the relevance of receptor and transporter polymorphisms. Br J Clin Pharmacol 77: 654‐72 [PMID:24354796]
Rudnick G. (2011) Cytoplasmic permeation pathway of neurotransmitter transporters. Biochemistry 50: 7462‐75 [PMID:21774491]
Rudnick G et al. (2014) The SLC6 transporters: perspectives on structure, functions, regulation, and models for transporter dysfunction. Pflugers Arch. 466: 25‐42 [PMID:24337881]
Vandenberg RJ et al. (2014) Glycine transport inhibitors for the treatment of pain. Trends Pharmacol. Sci. 35: 423‐30 [PMID:24962068]
Zhong H et al. (2012) Consideration of allosterism and interacting proteins in the physiological functions of the serotonin transporter. Biochem. Pharmacol. 83: 435‐42 [PMID:21983034]
SLC8 family of sodium/calcium exchangers
Overview
The sodium/calcium exchangers (NCX) use the extracellular sodium concentration to facilitate the extrusion of calcium out of the cell. Alongside the plasma membrane Ca2+‐ATPase (PMCA) and sarcoplasmic/endoplasmic reticulum Ca2+‐ATPase (SERCA), as well as the sodium/potassium/calcium exchangers (NKCX, SLC24 family), NCX allow recovery of intracellular calcium back to basal levels after cellular stimulation. When intracellular sodium ion levels rise, for example, following depolarisation, these transporters can operate in the reverse direction to allow calcium influx and sodium efflux, as an electrogenic mechanism. Structural modelling suggests the presence of 9 TM segments, with a large intracellular loop between the fifth and sixth TM segments.
| Nomenclature | Sodium/calcium exchanger 1 | Sodium/calcium exchanger 2 | Sodium/calcium exchanger 3 |
| Systematic nomenclature | SLC8A1 | SLC8A2 | SLC8A3 |
| Common abreviation | NCX1 | NCX2 | NCX3 |
| HGNC, UniProt | SLC8A1, P32418 | SLC8A2, Q9UPR5 | SLC8A3, P57103 |
| Stoichiometry | 3 Na+ (in) : 1 Ca2+ (out) or 4 Na+ (in) : 1 Ca2+ (out) [124]; Reverse mode 1 Ca2+ (in): 1 Na+ (out) | – | – |
Comments
Although subtype‐selective inhibitors of NCX function are not widely available, 3,4‐dichlorobenzamil and CBDMB act as non‐selective NCX inhibitors, while SEA0400, KB‐R7943, SN6, and ORM‐10103[256] act to inhibit NCX function with varying degrees of selectivity. BED is a selective NCX3 inhibitor [439].
Further Reading
Annunziato L et al. (2004) Pharmacology of brain Na+/Ca2+ exchanger: from molecular biology to therapeutic perspectives. Pharmacol. Rev. 56: 633‐54 [PMID:15602012]
Khananshvili D. (2014) Sodium‐calcium exchangers (NCX): molecular hallmarks underlying the tissue‐specific and systemic functions. Pflugers Arch. 466: 43‐60 [PMID:24281864]
Lytton J. (2007) Na+/Ca2+ exchangers: three mammalian gene families control Ca2+ transport. Biochem. J. 406: 365‐82 [PMID:17716241]
Quednau BD et al. (2004) The sodium/calcium exchanger family‐SLC8. Pflugers Arch. 447: 543‐8 [PMID:12734757]
Watanabe Y et al. (2006) Topics on the Na+/Ca2+ exchanger: pharmacological characterization of Na+/Ca2+ exchanger inhibitors. J. Pharmacol. Sci. 102: 7‐16 [PMID:16990699]
SLC9 family of sodium/hydrogen exchangers
Overview
Sodium/hydrogen exchangers or sodium/proton antiports are a family of transporters that maintain cellular pH by utilising the sodium gradient across the plasma membrane to extrude protons produced by metabolism, in a stoichiometry of 1 Na+ (in) : 1 H+(out). Several isoforms, NHE6, NHE7, NHE8 and NHE9 appear to locate on intracellular membranes [351, 357, 365]. Li+ and NH4 +, but not K+, ions may also be transported by some isoforms. Modelling of the topology of these transporters indicates 12 TM regions with an extended intracellular C‐terminus containing multiple regulatory sites.
NHE1 is considered to be a ubiquitously‐expressed ‘housekeeping’ transporter. NHE3 is highly expressed in the intestine and kidneys and regulate sodium movements in those tissues. NHE10 is present in sperm [504] and osteoclasts [307]; gene disruption results in infertile male mice [504].
Comments
Analogues of the non‐selective cation transport inhibitor amiloride appear to inhibit NHE function through competitive inhibition of the extracellular Na+ binding site. The more selective amiloride analogues MPA and ethylisopropylamiloride exhibit a rank order of affinity of inhibition of NHE1 > NHE2 > NHE3 [100, 480, 481].
Further Reading
Bobulescu IA et al. (2009) Luminal Na(+)/H (+) exchange in the proximal tubule. Pflugers Arch. 458: 5‐21 [PMID:18853182]
Casey JR et al. (2010) Sensors and regulators of intracellular pH. Nat. Rev. Mol. Cell Biol. 11: 50‐61 [PMID:19997129]
Christensen HL et al. (2013) Na(+) dependent acid‐base transporters in the choroid plexus; insights from slc4 and slc9 gene deletion studies. Front Physiol 4: 304 [PMID:24155723]
Donowitz M et al. (2013) SLC9/NHE gene family, a plasma membrane and organellar family of Na+/H+ exchangers. Mol. Aspects Med. 34: 236‐51 [PMID:23506868]
Kato A et al. (2011) Regulation of electroneutral NaCl absorption by the small intestine. Annu. Rev. Physiol. 73: 261‐81 [PMID:21054167]
Kemp G et al. (2008) Structure and function of the human Na+/H+ exchanger isoform 1. Channels (Austin) 2: 329‐36 [PMID:19001864]
Ohgaki R et al. (2011) Organellar Na+/H+ exchangers: novel players in organelle pH regulation and their emerging functions. Biochemistry 50: 443‐50 [PMID:21171650]
Parker MD et al. (2015) Na+‐H+ exchanger‐1 (NHE1) regulation in kidney proximal tubule. Cell. Mol. Life Sci. 72: 2061‐74 [PMID:25680790]
Ruffin VA et al. (2014) Intracellular pH regulation by acid‐base transporters in mammalian neurons. Front Physiol 5: 43 [PMID:24592239]
SLC10 family of sodium‐bile acid co‐transporters
Overview
The SLC10 family transport bile acids, sulphated solutes, and other xenobiotics in a sodium‐dependent manner. The founding members, SLC10A1 (NTCP) and SLC10A2 (ASBT) function, along with members of the ABC transporter family (MDR1/ABCB1, BSEP/ABCB11 and MRP2/ABCC2) and the organic solute transporter obligate heterodimer OSTα:OSTβ(SLC51), to maintain the enterohepatic circulation of bile acids [110, 281]. SLC10A6 (SOAT) functions as a sodium‐dependent transporter of sulphated solutes included sulfphated steroids and bile acids [187, 189]. Transport function has not yet been demonstrated for the 4 remaining members of the SLC10 family, SLC10A3 (P3), SLC10A4 (P4), SLC10A5 (P5), and SLC10A7 (P7), and the identity of their endogenous substrates remain unknown [160, 189, 193, 500]. Members of the SLC10 family are predicted to have seven transmembrane domains with an extracellular N‐terminus and cytoplasmic C‐terminus [29, 215].
Comments
Heterologously expressed SLC10A4 [188] or SLC10A7 [193] failed to exhibit significant transport of taurocholic acid, pregnenolone sulphate, dehydroepiandrosterone sulphate or choline. SLC10A4 has recently been suggested to associate with neuronal vesicles [68].
Further Reading
Anwer MS et al. (2014) Sodium‐dependent bile salt transporters of the SLC10A transporter family: more than solute transporters. Pflugers Arch. 466: 77‐89 [PMID:24196564]
Borges K. (2013) Slc10A4 ‐ what do we know about the function of this ~secret ligand carrier~ protein? Exp. Neurol. 248C: 258‐261 [PMID:23810836]
Claro da Silva T et al. (2013) The solute carrier family 10 (SLC10): beyond bile acid transport. Mol. Aspects Med. 34: 252‐69 [PMID:23506869]
Dawson PA et al. (2009) Bile acid transporters. J. Lipid Res. 50: 2340‐57 [PMID:19498215]
Döring B et al. (2012) The SLC10 carrier family: transport functions and molecular structure. Curr Top Membr 70: 105‐68 [PMID:23177985]
Zwicker BL et al. (2013) Transport and biological activities of bile acids. Int. J. Biochem. Cell Biol. 45: 1389‐98 [PMID:23603607]
SLC11 family of proton‐coupled metal ion transporters
Overview
The family of proton‐coupled metal ion transporters are responsible for movements of divalent cations, particularly ferrous and manganese ions, across the cell membrane (SLC11A2/DMT1) and across endosomal (SLC11A2/DMT1) or lysosomal/phagosomal membranes (SLC11A1/NRAMP1), dependent on proton transport. Both proteins appear to have 12 TM regions and cytoplasmic N‐ and C‐ termini. NRAMP1 is involved in antimicrobial action in macrophages, although its precise mechanism is undefined. Facilitated diffusion of divalent cations into phagosomes may increase intravesicular free radicals to damage the pathogen. Alternatively, export of divalent cations from the phagosome may deprive the pathogen of essential enzyme cofactors. SLC11A1/DMT1 is more widely expressed and appears to assist in divalent cation assimilation from the diet, as well as in phagocytotic cells.
Comments
Loss‐of‐function mutations in NRAMP1 are associated with increased susceptibility to microbial infection (OMIM: 607948). Loss‐of‐function mutations in DMT1 are associated with microcytic anemia (OMIM: 206100).
Further Reading
Codazzi F et al. (2015) Iron entry in neurons and astrocytes: a link with synaptic activity. Front Mol Neurosci 8: 18 [PMID:26089776]
Li X et al. (2011) SLC11A1 (NRAMP1) polymorphisms and tuberculosis susceptibility: updated systematic review and meta‐analysis. PLoS ONE 6: e15831 [PMID:21283567]
Mackenzie B et al. (2004) SLC11 family of H+‐coupled metal‐ion transporters NRAMP1 and DMT1. Pflugers Arch. 447: 571‐9 [PMID:14530973]
Montalbetti N et al. (2013) Mammalian iron transporters: families SLC11 and SLC40. Mol. Aspects Med. 34: 270‐87 [PMID:23506870]
Nevo Y et al. (2006) The NRAMP family of metal‐ion transporters. Biochim. Biophys. Acta 1763: 609‐20 [PMID:16908340]
Skjørringe T et al. (2015) Divalent metal transporter 1 (DMT1) in the brain: implications for a role in iron transport at the blood‐brain barrier, and neuronal and glial pathology. Front Mol Neurosci 8: 19 [PMID:26106291]
Wessling‐Resnick M. (2015) Nramp1 and Other Transporters Involved in Metal Withholding during Infection. J. Biol. Chem. 290: 18984‐90 [PMID:26055722]
Zheng W et al. (2012) Regulation of brain iron and copper homeostasis by brain barrier systems: implication in neurodegenerative diseases. Pharmacol. Ther. 133: 177‐88 [PMID:22115751]
SLC12 family of cation‐coupled chloride transporters
Overview
The SLC12 family of chloride transporters contribute to ion fluxes across a variety of tissues, particularly in the kidney and choroid plexus of the brain. Within this family, further subfamilies are identifiable: NKCC1, NKCC2 and NCC constitute a group of therapeutically‐relevant transporters, targets for loop and thiazide diuretics. These 12 TM proteins exhibit cytoplasmic termini and an extended extracellular loop at TM7/8 and are kidney‐specific (NKCC2 and NCC) or show a more widespread distribution (NKCC1). A second family, the K‐Cl co‐transporters are also 12 TM domain proteins with cytoplasmic termini, but with an extended extracellular loop at TM 5/6. CCC6 exhibits structural similarities with the K‐Cl co‐transporters, while CCC9 is divergent, with 11 TM domains and a cytoplasmic N‐terminus and extracellular C‐terminus.
| Nomenclature | Kidney‐specific Na‐K‐Cl symporter | Basolateral Na‐K‐Cl symporter | Na‐Cl symporter | K‐Cl cotransporter 1 |
| Systematic nomenclature | SLC12A1 | SLC12A2 | SLC12A3 | SLC12A4 |
| Common abreviation | NKCC2 | NKCC1 | NCC | KCC1 |
| HGNC, UniProt | SLC12A1, Q13621 | SLC12A2, P55011 | SLC12A3, P55017 | SLC12A4, Q9UP95 |
| Stoichiometry | 1 Na+ : 1 K+ : 2 Cl‐ (in) | 1 Na+ : 1 K+ : 2 Cl‐ (in) | 1 Na+ : 1 Cl‐ (in) | 1 K+ : 1 Cl‐ (out) |
| Inhibitors | bumetanide (pIC50 6.5) [220], piretanide (pIC50 6) [220], furosemide (pIC50 5.2) [220] | piretanide (pIC50 5.6) [220], bumetanide (pIC50 5.6) [220], furosemide (pIC50 5.1) [220] | chlorothiazide, cyclothiazide, hydrochlorothiazide, metolazone | DIOA |
| Nomenclature | K‐Cl cotransporter 2 | K‐Cl cotransporter 3 | K‐Cl cotransporter 4 | Cation‐chloride cotransporter 9 |
| Systematic nomenclature | SLC12A5 | SLC12A6 | SLC12A7 | SLC12A8 |
| Common abreviation | KCC2 | KCC3 | KCC4 | CCC9 |
| HGNC, UniProt | SLC12A5, Q9H2X9 | SLC12A6, Q9UHW9 | SLC12A7, Q9Y666 | SLC12A8, A0AV02 |
| Substrates | – | – | – | L‐glutamic acid, spermine, L‐aspartic acid, spermidine |
| Stoichiometry | 1 K+ : 1 Cl‐ (out) | 1 K+ : 1 Cl‐ (out) | 1 K+ : 1 Cl‐ (out) | Unknown |
| Inhibitors | VU0240551 (pIC50 6.2) [114], DIOA | DIOA | DIOA | – |
Comments
DIOA is able to differentiate KCC isoforms from NKCC and NCC transporters, but also inhibits CFTR [250].
Further Reading
Arroyo JP et al. (2013) The SLC12 family of electroneutral cation‐coupled chloride cotransporters. Mol. Aspects Med. 34: 288‐98 [PMID:23506871]
Castrop H et al. (2014) Physiology and pathophysiology of the renal Na‐K‐2Cl cotransporter (NKCC2). Am. J. Physiol. Renal Physiol. 307: F991‐F1002 [PMID:25186299]
Gagnon KB et al. (2013) Physiology of SLC12 transporters: lessons from inherited human genetic mutations and genetically engineered mouse knockouts. Am. J. Physiol., Cell Physiol. 304: C693‐714 [PMID:23325410]
Gamba G et al. (2009) Thick ascending limb: the Na(+):K (+):2Cl (‐) co‐transporter, NKCC2, and the calcium‐sensing receptor, CaSR. Pflugers Arch. 458: 61‐76 [PMID:18982348]
Hebert SC et al. (2004) Molecular physiology of cation‐coupled Cl‐ cotransport: the SLC12 family. Pflugers Arch. 447: 580‐93 [PMID:12739168]
Kahle KT et al. (2015) K‐Cl cotransporters, cell volume homeostasis, and neurological disease. Trends Mol Med [PMID:26142773]
Kahle KT et al. (2010) Phosphoregulation of the Na‐K‐2Cl and K‐Cl cotransporters by the WNK kinases. Biochim. Biophys. Acta 1802: 1150‐8 [PMID:20637866]
Lang F et al. (2007) Functional significance of channels and transporters expressed in the inner ear and kidney. Am. J. Physiol., Cell Physiol. 293: C1187‐208 [PMID:17670895]
Löscher W et al. (2013) Cation‐chloride cotransporters NKCC1 and KCC2 as potential targets for novel antiepileptic and antiepileptogenic treatments. Neuropharmacology 69: 62‐74 [PMID:22705273]
Markadieu N et al. (2014) Physiology and pathophysiology of SLC12A1/2 transporters. Pflugers Arch. 466: 91‐105 [PMID:24097229]
Moes AD et al. (2014) The sodium chloride cotransporter SLC12A3: new roles in sodium, potassium, and blood pressure regulation. Pflugers Arch. 466: 107‐18 [PMID:24310820]
SLC13 family of sodium‐dependent sulphate/carboxylate transporters
Overview
Within the SLC13 family, two groups of transporters may be differentiated on the basis of the substrates transported: NaS1 and NaS2 convey sulphate, while NaC1‐3 transport carboxylates. NaS1 and NaS2 transporters are made up of 13 TM domains, with an intracellular N terminus and are electrogenic with physiological roles in the intestine, kidney and placenta. NaC1, NaC2 and NaC3 are made up of 11 TM domains with an intracellular N terminus and are electrogenic, with physiological roles in the kidney and liver.
| Nomenclature | Na+/sulfate | Na+/dicarboxylate | Na+/dicarboxylate | Na+/sulfate | Na+/citrate |
| cotransporter | cotransporter 1 | cotransporter 3 | cotransporter | cotransporter | |
| Systematic nomenclature | SLC13A1 | SLC13A2 | SLC13A3 | SLC13A4 | SLC13A5 |
| Common abreviation | NaS1 | NaC1 | NaC3 | NaS2 | NaC2 |
| HGNC, UniProt | SLC13A1, Q9BZW2 | SLC13A2, Q13183 | SLC13A3, Q8WWT9 | SLC13A4, Q9UKG4 | SLC13A5, Q86YT5 |
| Endogenous substrates | SeO4 2‐, SO4 2‐, S2O3 2‐ | citric acid, succinic acid | citric acid, succinic acid | SO4 2‐ | citric acid, pyruvic acid |
| Stoichiometry | 3 Na+ : 1 SO4 2‐ (in) | 3 Na+ : 1 dicarboxylate2‐ (in) | Unknown | 3 Na+ : SO4 2‐ (in) | Unknown |
Further Reading
Markovich D. (2014) Na+‐sulfate cotransporter SLC13A1. Pflugers Arch. 466: 131‐7 [PMID:24193406]
Pajor AM. (2014) Sodium‐coupled dicarboxylate and citrate transporters from the SLC13 family. Pflugers Arch. 466: 119‐30 [PMID:24114175]
SLC14 family of facilitative urea transporters
Overview
As a product of protein catabolism, urea is moved around the body and through the kidneys for excretion. Although there is experimental evidence for concentrative urea transporters, these have not been defined at the molecular level. The SLC14 family are facilitative transporters, allowing urea movement down its concentration gradient. Multiple splice variants of these transporters have been identified; for UT‐A transporters, in particular, there is evidence for cell‐specific expression of these variants with functional impact [455]. Topographical modelling suggests that the majority of the variants of SLC14 transporters have 10 TM domains, with a glycosylated extracellular loop at TM5/6, and intracellular C‐ and N‐termini. The UT‐A1 splice variant, exceptionally, has 20 TM domains, equivalent to a combination of the UT‐A2 and UT‐A3 splice variants.
| Nomenclature | Erythrocyte urea transporter | Kidney urea transporter |
| Systematic nomenclature | SLC14A1 | SLC14A2 |
| Common abreviation | UT‐B | UT‐A |
| HGNC, UniProt | SLC14A1, Q13336 | SLC14A2, Q15849 |
| Substrates | acetamide [546], acrylamide [546], methylurea [546] | – |
| Endogenous substrates | ammonium carbonate [546], urea [546], formamide [546] | urea [328] |
| Stoichiometry | Equilibrative | Equilibrative |
Further Reading
Esteva‐Font C et al. (2015) Urea transporter proteins as targets for small‐molecule diuretics. Nat Rev Nephrol 11: 113‐23 [PMID:25488859]
LeMoine CM et al. (2015) Evolution of urea transporters in vertebrates: adaptation to urea's multiple roles and metabolic sources. J. Exp. Biol. 218: 1936‐1945 [PMID:26085670]
Pannabecker TL. (2013) Comparative physiology and architecture associated with the mammalian urine concentrating mechanism: role of inner medullary water and urea transport pathways in the rodent medulla. Am. J. Physiol. Regul. Integr. Comp. Physiol. 304: R488‐503 [PMID:23364530]
Shayakul C et al. (2013) The urea transporter family (SLC14): physiological, pathological and structural aspects. Mol. Aspects Med. 34: 313‐22 [PMID:23506873]
Shayakul C et al. (2004) The SLC14 gene family of urea transporters. Pflugers Arch. 447: 603‐9 [PMID:12856182]
Smith CP. (2009) Mammalian urea transporters. Exp. Physiol. 94: 180‐5 [PMID:19028811]
Stewart G. (2011) The emerging physiological roles of the SLC14A family of urea transporters. Br. J. Pharmacol. 164: 1780‐92 [PMID:21449978]
SLC15 family of peptide transporters
Overview
The SLC15 family of peptide transporters may be divided on the basis of structural and functional differences into two subfamilies: SLC15A1 (PepT1) and SLC15A2 (PepT2) transport di‐ and tripeptides, but not amino acids, whereas SLC15A3 (PHT2) and SLC15A4 (PHT1) transport L‐histidine and some di‐ and tripeptides [105]. The transporters are 12 TM proteins with intracellular termini and an extended extracellular loop at TM 9/10. The crystal structure of PepTSo (a prokaryote homologue of PepT1 and PepT2 from Shewanella oneidensis) confirms many of the predicted structural features of mammalian PepT1 and PepT2 [360].
PHT1 has been suggested to be intracellular [410], while PHT2 protein is located on lysosomes in transfected cells [52, 230, 426]. PHT1 is hypothesised to mediate efflux of bacterial‐derived peptides into the cytosol perhaps in the colon where SLC15A4 mRNA expression is increased in inflammatory bowel disease [305]. Transport via PHT1 may be important in immune responses as both Toll‐like receptor‐ and NOD1‐mediated responses are reduced in PHT1 knockout mice or mouse strains expressing mutations in PHT1 [45, 430].
Comments
The PepT1 and PepT2 transporters are particularly promiscuous in the transport of dipeptides and tripeptides from the endogenous amino acids, as well as some D‐amino acid containing peptides. PepT1 has also been exploited to allow delivery of therapeutic pro‐drugs, such as those for zidovudine (zidovudine) [218], sulpiride[508] and cytarabine[457].
D‐Ala‐Lys‐AMCA has been used as a fluorescent probe to identify transport via both PepT1 and PepT2 [416] .
Further Reading
Anderson CM et al. (2010) Hijacking solute carriers for proton‐coupled drug transport. Physiology (Bethesda) 25: 364‐77 [PMID:21186281]
Biegel A et al. (2006) The renal type H+/peptide symporter PEPT2: structure‐affinity relationships. Amino Acids 31: 137‐56 [PMID:16868651]
Brandsch M. (2009) Transport of drugs by proton‐coupled peptide transporters: pearls and pitfalls. Expert Opin Drug Metab Toxicol 5: 887‐905 [PMID:19519280]
Ingersoll SA et al. (2012) The role and pathophysiological relevance of membrane transporter PepT1 in intestinal inflammation and inflammatory bowel disease. Am. J. Physiol. Gastrointest. Liver Physiol. 302: G484‐92 [PMID:22194420]
Newstead S. (2015) Molecular insights into proton coupled peptide transport in the PTR family of oligopeptide transporters. Biochim. Biophys. Acta 1850: 488‐499 [PMID:24859687]
Smith DE et al. (2013) Proton‐coupled oligopeptide transporter family SLC15: physiological, pharmacological and pathological implications. Mol. Aspects Med. 34: 323‐36 [PMID:23506874]
Thwaites DT et al. (2007) H+‐coupled nutrient, micronutrient and drug transporters in the mammalian small intestine. Exp. Physiol. 92: 603‐19 [PMID:17468205]
SLC16 family of monocarboxylate transporters
Overview
Members of the SLC16 family may be divided into subfamilies on the basis of substrate selectivities, particularly lactate (e.g. L‐lactic acid), pyruvic acid and ketone bodies, as well as aromatic amino acids. Topology modelling suggests 12 TM domains, with intracellular termini and an extended loop at TM 6/7.
The proton‐coupled monocarboxylate transporters (monocarboxylate transporters 1, 4, 2 and 3) allow transport of the products of cellular metabolism, principally lactate (e.g. L‐lactic acid) and pyruvic acid.
| Nomenclature | Monocarboxylate transporter 1 | Monocarboxylate transporter 2 | Monocarboxylate transporter 3 | Monocarboxylate transporter 4 |
| Systematic nomenclature | SLC16A1 | SLC16A7 | SLC16A8 | SLC16A3 |
| Common abreviation | MCT1 | MCT2 | MCT3 | MCT4 |
| HGNC, UniProt | SLC16A1, P53985 | SLC16A7, O60669 | SLC16A8, O95907 | SLC16A3, O15427 |
| Substrates | γ‐hydroxybutyric acid [506] | – | – | – |
| Endogenous substrates | pyruvic acid, L‐lactic acid, β‐D‐hydroxybutyric acid | pyruvic acid, L‐lactic acid | L‐lactic acid | pyruvic acid, L‐lactic acid |
| Stoichiometry | 1 H+ : 1 monocarboxylate‐ (out) | 1 H+ : 1 monocarboxylate‐ (out) | 1 H+ : 1 monocarboxylate‐ (out) | 1 H+ : 1 monocarboxylate‐ (out) |
| Nomenclature | Monocarboxylate transporter 6 | Monocarboxylate transporter 8 | Monocarboxylate transporter 10 |
| Systematic nomenclature | SLC16A5 | SLC16A2 | SLC16A10 |
| Common abreviation | MCT6 | MCT8 | TAT1 |
| HGNC, UniProt | SLC16A5, O15375 | SLC16A2, P36021 | SLC16A10, Q8TF71 |
| Endogenous substrates | – | triiodothyronine [169], T4 [169] | L‐tryptophan, L‐phenylalanine, levodopa, L‐tyrosine |
| Stoichiometry | Unknown | Unknown | Unknown |
| Comments | MCT6 has been reported to transport bumetanide, but not short chain fatty acids [353]. | – | – |
Comments
MCT1 and MCT2, but not MCT3 and MCT4, are inhibited by CHC, which also inhibits members of the mitochondrial transporter family, SLC25.
MCT5‐MCT7, MCT9 and MCT11‐14 are regarded as orphan transporters.
Further Reading
Bernal J et al. (2015) Thyroid hormone transporters‐functions and clinical implications. Nat Rev Endocrinol 11: 406‐417 [PMID:25942657]
SLC17 phosphate and organic anion transporter family
Overview
The SLC17 family are sometimes referred to as Type I sodium‐phosphate co‐transporters, alongside Type II (SLC34 family) and Type III (SLC20 family) transporters. Within the SLC17 family, however, further subgroups of organic anion transporters may be defined, allowing the accumulation of sialic acid in the endoplasmic reticulum and glutamate (e.g. L‐glutamic acid) or nucleotides in synaptic and secretory vesicles. Topology modelling suggests 12 TM domains.
Type I sodium‐phosphate co‐transporters
Overview
Type I sodium‐phosphate co‐transporters are expressed in the kidney and intestine.
| Nomenclature | Sodium/phosphate | Sodium/phosphate | Sodium/phosphate | Sodium/phosphate |
| cotransporter 1 | cotransporter 3 | cotransporter 4 | cotransporter homolog | |
| Systematic nomenclature | SLC17A1 | SLC17A2 | SLC17A3 | SLC17A4 |
| Common abreviation | NPT1 | NPT3 | NPT4 | – |
| HGNC, UniProt | SLC17A1, Q14916 | SLC17A2, O00624 | SLC17A3, O00476 | SLC17A4, Q9Y2C5 |
| Substrates | probenecid [69], penicillin G [69], Cl‐ [240], organic acids [240], uric acid [240], phosphate [240] | – | – | – |
| Stoichiometry | Unknown | Unknown | Unknown | Unknown |
Sialic acid transporter
Overview
The sialic acid transporter is expressed on both lysosomes and synaptic vesicles, where it appears to allow export of sialic acid and accumulation of acidic amino acids, respectively [349], driven by proton gradients. In lysosomes, degradation of glycoproteins generates amino acids and sugar residues, which are metabolized further following export from the lysosome.
| Nomenclature | Sialin |
| Systematic nomenclature | SLC17A5 |
| Common abreviation | AST |
| HGNC, UniProt | SLC17A5, Q9NRA2 |
| Endogenous substrates | L‐lactic acid, gluconate (out), L‐glutamic acid (in) [349], glucuronic acid, L‐aspartic acid [349], sialic acid |
| Stoichiometry | 1 H+ : 1 sialic acid (out) |
Comments
Loss‐of‐function mutations in sialin are associated with Salla disease (OMIM: 604369), an autosomal recessive neurodegenerative disorder associated with sialic acid storage disease [497].
Vesicular glutamate transporters (VGLUTs)
Overview
Vesicular glutamate transporters (VGLUTs) allow accumulation of glutamate into synaptic vesicles, as well as secretory vesicles in endocrine tissues. The roles of VGLUTs in kidney and liver are unclear. These transporters appear to utilize the proton gradient and also express a chloride conductance [33].
| Nomenclature | Vesicular glutamate transporter 1 | Vesicular glutamate transporter 2 | Vesicular glutamate transporter 3 |
| Systematic nomenclature | SLC17A7 | SLC17A6 | SLC17A8 |
| Common abreviation | VGLUT1 | VGLUT2 | VGLUT3 |
| HGNC, UniProt | SLC17A7, Q9P2U7 | SLC17A6, Q9P2U8 | SLC17A8, Q8NDX2 |
| Endogenous substrates | L‐glutamic acid>D‐glutamic acid | L‐glutamic acid>D‐glutamic acid | L‐glutamic acid>D‐glutamic acid |
| Stoichiometry | Unknown | Unknown | Unknown |
Comments
Endogenous ketoacids produced during fasting have been proposed to regulate VGLUT function through blocking chloride ion‐mediated allosteric enhancement of transporter function [258].
Vesicular nucleotide transporter
Overview
The vesicular nucleotide transporter is the most recent member of the SLC17 family to have an assigned function. Uptake of ATP was independent of pH, but dependent on chloride ions and membrane potential [431].
| Nomenclature | Vesicular nucleotide transporter |
| Systematic nomenclature | SLC17A9 |
| Common abreviation | VNUT |
| HGNC, UniProt | SLC17A9, Q9BYT1 |
| Endogenous substrates | guanosine 5'‐diphosphate [431], guanosine‐5'‐triphosphate [431], ATP [431] |
| Stoichiometry | Unknown |
Comments
VGLUTs and VNUT can be inhibited by DIDS and evans blue dye.
Further Reading
Biber J et al. (2013) Phosphate transporters and their function. Annu. Rev. Physiol. 75: 535‐50 [PMID:23398154]
El Mestikawy S et al. (2011) From glutamate co‐release to vesicular synergy: vesicular glutamate transporters. Nat. Rev. Neurosci. 12: 204‐16 [PMID:21415847]
Marks J et al. (2010) Phosphate homeostasis and the renal‐gastrointestinal axis. Am. J. Physiol. Renal Physiol. 299: F285‐96 [PMID:20534868]
Miyamoto K et al. (2011) Sodium‐dependent phosphate cotransporters: lessons from gene knockout and mutation studies. J Pharm Sci 100: 3719‐30 [PMID:21567407]
Omote H et al. (2011) Vesicular neurotransmitter transporter: bioenergetics and regulation of glutamate transport. Biochemistry 50: 5558‐65 [PMID:21612282]
Reimer RJ. (2013) SLC17: a functionally diverse family of organic anion transporters. Mol. Aspects Med. 34: 350‐9 [PMID:23506876]
Shobeiri N et al. (2013) Phosphate: an old bone molecule but new cardiovascular risk factor. Br J Clin Pharmacol [PMID:23506202]
SLC18 family of vesicular amine transporters
Overview
The vesicular amine transporters (VATs) are putative 12 TM domain proteins that function to transport singly positively charged amine neurotransmitters and hormones from the cytoplasm and concentrate them within secretory vesicles. They function as amine/proton antiporters driven by secondary active transport utilizing the proton gradient established by a multi‐subunit vacuolar ATPase that acidifies secretory vesicles (reviewed by [139]). The vesicular acetylcholine transporter (VAChT; [148]) localizes to cholinergic neurons, but non‐neuronal expression has also been claimed [434]. Vesicular monoamine transporter 1 (VMAT1, [146]) is mainly expressed in peripheral neuroendocrine cells, but most likely not in the CNS, whereas VMAT2 [147] distributes between both central and peripheral sympathetic monoaminergic neurones [140].
| Nomenclature | Vesicular monoamine | Vesicular monoamine | Vesicular acetylcholine | solute carrier family 18, |
| transporter 1 | transporter 2 | transporter | subfamily B, member 1 | |
| Systematic nomenclature | SLC18A1 | SLC18A2 | SLC18A3 | SLC18B1 |
| Common abreviation | VMAT1 | VMAT2 | VAChT | – |
| HGNC, UniProt | SLC18A1, P54219 | SLC18A2, Q05940 | SLC18A3, Q16572 | Q6NT16 |
| Substrates | dexamfetamine (K i4.7 × 10−5M) [147], β‐phenylethylamine (K i3.4 × 10−5M) [147], fenfluramine (K i3.1 × 10−6M) [147], MPP+ (K i6.9 × 10−5M) [147], MDMA (K i1.9 × 10−5M) [147] | β‐phenylethylamine (K i3.7 × 10−6M) [147], dexamfetamine (K i2.1 × 10−6M) [147], fenfluramine (K i5.1 × 10−6M) [147], MPP+ (K i8.9 × 10−6M) [147], MDMA (K i6.9 × 10−6M) [147] | TPP+ [56], ethidium [56], N‐methyl‐pyridinium‐2‐aldoxime [56], N‐(4'‐pentanonyl)‐4‐(4”‐ dimethylamino‐styryl)pyridinium [56] | – |
| Endogenous substrates | histamine (K i4.6 × 10−3M) [147], 5‐hydroxytryptamine (K i1.4 × 10−6M) [147], dopamine (K i3.8 × 10−6M) [147], (‐)‐noradrenaline (K i1.3 × 10−5M) [147], (‐)‐adrenaline (K i5.5 × 10−6M) [147] | histamine (K i1.4 × 10−4M) [147], dopamine (K i1.4 × 10−6M) [147], 5‐hydroxytryptamine (K i9 × 10−7M) [147], (‐)‐noradrenaline (K i3.4 × 10−6M) [147], (‐)‐adrenaline (K i1.9 × 10−6M) [147] | acetylcholine (K i7.9 × 10−4M) [57, 276], choline (K i5 × 10−4M) [57, 276] | – |
| Stoichiometry | 1 amine (in): 2H+ (out) | 1 amine (in): 2H+ (out) | 1 amine (in): 2H+ (out) | – |
| Inhibitors | reserpine (pK i 7.5) [147], ketanserin (pK i 5.8) [147], tetrabenazine (pK i 4.7) [147] | reserpine (pK i 7.9) [147], tetrabenazine (pK i 7) [147], ketanserin (pK i 6.3) [147] | aminobenzovesamicol (pK i 10.9) [138], vesamicol (pK i 8.7) [138] | – |
| Labelled ligands | – | [3H]TBZOH (Inhibitor) (pK d 8.2) [495], [125I]iodovinyl‐TBZ (Inhibitor) (pK d 8.1) [293], [11C]DTBZ (Inhibitor), [125I]7‐azido‐8‐iodoketanserine (Inhibitor) [449] | [3H]vesamicol (pK d 8.4) [495], [123I]iodobenzovesamicol | – |
Comments
pKi values for endogenous and synthetic substrate inhibitors of human VMAT1 and VMAT2 are for inhibition of [3H]5‐HT uptake in transfected and permeabilised CV‐1 cells as detailed by [147]. In addition to the monoamines listed in the table, the trace amines tyramine and β‐phenylethylamine are probable substrates for VMAT2 [140]. Probes listed in the table are those currently employed; additional agents have been synthesized (e.g. [551]).
Further Reading
Anne C et al. (2014) Vesicular neurotransmitter transporters: mechanistic aspects. Curr Top Membr 73: 149‐74 [PMID:24745982]
Chaudhry FA et al. (2008) Vesicular neurotransmitter transporters as targets for endogenous and exogenous toxic substances. Annu. Rev. Pharmacol. Toxicol. 48: 277‐301 [PMID:17883368]
Eiden LE et al. (2011) VMAT2: a dynamic regulator of brain monoaminergic neuronal function interacting with drugs of abuse. Ann. N. Y. Acad. Sci. 1216: 86‐98 [PMID:21272013]
Giboureau N et al. (2010) PET radioligands for the vesicular acetylcholine transporter (VAChT). Curr Top Med Chem 10: 1569‐83 [PMID:20583990]
Khare P et al. (2010) Equilibrium binding and transport by vesicular acetylcholine transporter. Methods Mol. Biol. 637: 181‐219 [PMID:20419436]
Lawal HO et al. (2013) SLC18: Vesicular neurotransmitter transporters for monoamines and acetylcholine. Mol. Aspects Med. 34: 360‐72 [PMID:23506877]
Prado VF et al. (2013) Regulation of cholinergic activity by the vesicular acetylcholine transporter. Biochem. J. 450: 265‐74 [PMID:23410039]
Ramamoorthy S et al. (2011) Regulation of monoamine transporters: Role of transporter phosphorylation. Pharmacol. Ther. 129: 220‐38 [PMID:20951731]
Wimalasena K. (2011) Vesicular monoamine transporters: structure‐function, pharmacology, and medicinal chemistry. Med Res Rev 31: 483‐519 [PMID:20135628]
SLC19 family of vitamin transporters
Overview
The B vitamins folic acid and thiamine are transported across the cell membrane, particularly in the intestine, kidneys and placenta, using pH differences as driving forces. Topological modelling suggests the transporters have 12 TM domains.
| Nomenclature | Reduced folate transporter 1 | Thiamine transporter 1 | Thiamine transporter 2 |
| Systematic nomenclature | SLC19A1 | SLC19A2 | SLC19A3 |
| Common abreviation | FOLT | ThTr1 | ThTr2 |
| HGNC, UniProt | SLC19A1, P41440 | SLC19A2, O60779 | SLC19A3, Q9BZV2 |
| Substrates | N5‐formyltetrahydrofolate, folinic acid, methotrexate, folic acid [389] | – | – |
| Endogenous substrates | Other tetrahydrofolate‐cofactors, Organic phosphates; in particular, adenine nucleotides, tetrahydrofolic acid [389], N5‐methylfolate [389], thiamine monophosphate [547] | thiamine | thiamine |
| Stoichiometry | Folate (in) : organic phosphate (out), precise stoichiometry unknown | A facilitative carrier not known to be coupled to an inorganic or organic ion gradient | A facilitative carrier not known to be coupled to an inorganic or organic ion gradient |
| Labelled ligands | [3H]folic acid [19], [3H]methotrexate [19] | [3H]thiamine [134] | [3H]thiamine [399] |
Comments
Loss‐of‐function mutations in ThTr1 underlie thiamine‐responsive megaloblastic anemia syndrome [119].
Further Reading
Ganapathy V et al. (2004) SLC19: the folate/thiamine transporter family. Pflugers Arch. 447: 641‐6 [PMID:14770311]
Goldman ID et al. (2010) The antifolates: evolution, new agents in the clinic, and how targeting delivery via specific membrane transporters is driving the development of a next generation of folate analogs. Curr Opin Investig Drugs 11: 1409‐23 [PMID:21154123]
Hou Z et al. (2014) Biology of the major facilitative folate transporters SLC19A1 and SLC46A1. Curr Top Membr 73: 175‐204 [PMID:24745983]
Matherly LH et al. (2008) Structure and function of the reduced folate carrier a paradigm of a major facilitator superfamily mammalian nutrient transporter. Vitam. Horm. 79: 145‐84 [PMID:18804694]
Matherly LH et al. (2014) The major facilitative folate transporters solute carrier 19A1 and solute carrier 46A1: biology and role in antifolate chemotherapy of cancer. Drug Metab. Dispos. 42: 632‐49 [PMID:24396145]
Yuasa H et al. (2009) Molecular and functional characteristics of proton‐coupled folate transporter. J Pharm Sci 98: 1608‐16 [PMID:18823045]
Zhao R et al. (2011) Mechanisms of membrane transport of folates into cells and across epithelia. Annu. Rev. Nutr. 31: 177‐201 [PMID:21568705]
Zhao R et al. (2013) Folate and thiamine transporters mediated by facilitative carriers (SLC19A1‐3 and SLC46A1) and folate receptors. Mol. Aspects Med. 34: 373‐85 [PMID:23506878]
SLC20 family of sodium‐dependent phosphate transporters
Overview
The SLC20 family is looked upon not only as ion transporters, but also as retroviral receptors. As ion transporters, they are sometimes referred to as Type III sodium‐phosphate co‐transporters, alongside Type I (SLC17 family) and Type II (SLC34 family). PiTs are cell‐surface transporters, composed of ten TM domains with extracellular C‐ and N‐termini. PiT1 is a focus for dietary phosphate and vitamin D regulation of parathyroid hormone secretion from the parathyroid gland. PiT2 appears to be involved in intestinal absorption of dietary phosphate.
| Nomenclature | Sodium‐dependent phosphate transporter 1 | Sodium‐dependent phosphate transporter 2 |
| Systematic nomenclature | SLC20A1 | SLC20A2 |
| Common abreviation | PiT1 | PiT2 |
| HGNC, UniProt | SLC20A1, Q8WUM9 | SLC20A2, Q08357 |
| Substrates | AsO4 3‐ [400], phosphate [400] | phosphate [400] |
| Stoichiometry | >1 Na+ : 1 HPO4 2‐ (in) | >1 Na+ : 1 HPO4 2‐ (in) |
Further Reading
Biber J et al. (2013) Phosphate transporters and their function. Annu. Rev. Physiol. 75: 535‐50 [PMID:23398154]
Forster IC et al. (2013) Phosphate transporters of the SLC20 and SLC34 families. Mol. Aspects Med. 34: 386‐95 [PMID:23506879]
Marks J et al. (2010) Phosphate homeostasis and the renal‐gastrointestinal axis. Am. J. Physiol. Renal Physiol. 299: F285‐96 [PMID:20534868]
Miyamoto K et al. (2011) Sodium‐dependent phosphate cotransporters: lessons from gene knockout and mutation studies. J Pharm Sci 100: 3719‐30 [PMID:21567407]
Shobeiri N et al. (2013) Phosphate: an old bone molecule but new cardiovascular risk factor. Br J Clin Pharmacol [PMID:23506202]
SLC22 family of organic cation and anion transporters
Overview
The SLC22 family of transporters is mostly composed of non‐selective transporters, which are expressed highly in liver, kidney and intestine, playing a major role in drug disposition. The family may be divided into three subfamilies based on the nature of the substrate transported: organic cations (OCTs), organic anions (OATs) and organic zwiterrion/cations (OCTN). Membrane topology is predicted to contain 12 TM domains with intracellular termini, and an extended extracellular loop at TM 1/2.
Further Reading
Burckhardt G. (2012) Drug transport by Organic Anion Transporters (OATs). Pharmacol. Ther. 136: 106‐30 [PMID:22841915]
Koepsell H. (2013) The SLC22 family with transporters of organic cations, anions and zwitterions. Mol. Aspects Med. 34: 413‐35 [PMID:23506881]
König J et al. (2013) Transporters and drug‐drug interactions: important determinants of drug disposition and effects. Pharmacol. Rev. 65: 944‐66 [PMID:23686349]
Motohashi H et al. (2013) Organic cation transporter OCTs (SLC22) and MATEs (SLC47) in the human kidney. AAPS J 15: 581‐8 [PMID:23435786]
Organic cation transporters (OCT)
Overview
Organic cation transporters (OCT) are electrogenic, Na+‐independent and reversible.
| Nomenclature | Organic cation transporter 1 | Organic cation transporter 2 | Organic cation transporter 3 |
| Systematic nomenclature | SLC22A1 | SLC22A2 | SLC22A3 |
| Common abreviation | OCT1 | OCT2 | OCT3 |
| HGNC, UniProt | SLC22A1, O15245 | SLC22A2, O15244 | SLC22A3, O75751 |
| Substrates | MPP+, tetraethylammonium, desipramine, metformin, aciclovir | MPP+ [198], pancuronium [198], tetraethylammonium [198], tubocurarine [198] | MPP+, tetraethylammonium, quinidine |
| Endogenous substrates | PGF2α, choline, PGE2, 5‐hydroxytryptamine | PGE2 [280], dopamine [209], histamine [209] | (‐)‐noradrenaline [550], dopamine [550], 5‐hydroxytryptamine [550] |
| Stoichiometry | Unknown | Unknown | Unknown |
Comments
corticosterone and quinine are able to inhibit all three organic cation transporters.
Further Reading
A‐González N et al. (2011) Liver X receptors as regulators of macrophage inflammatory and metabolic pathways. Biochim. Biophys. Acta 1812: 982‐94 [PMID:21193033]
Lozano E et al. (2013) Role of the plasma membrane transporter of organic cations OCT1 and its genetic variants in modern liver pharmacology. Biomed Res Int 2013: 692071 [PMID:23984399]
Pelis RM et al. (2014) SLC22, SLC44, and SLC47 transporters–organic anion and cation transporters: molecular and cellular properties. Curr Top Membr 73: 233‐61 [PMID:24745985]
Organic zwitterions/cation transporters (OCTN)
Overview
Organic zwitterions/cation transporters (OCTN) function as organic cation uniporters, organic cation/proton exchangers or sodium/L‐carnitine co‐transporters.
| Nomenclature | Organic cation/carnitine transporter 1 | Organic cation/carnitine transporter 2 | Carnitine transporter 2 |
| Systematic nomenclature | SLC22A4 | SLC22A5 | SLC22A16 |
| Common abreviation | OCTN1 | OCTN2 | CT2 |
| HGNC, UniProt | SLC22A4, Q9H015 | SLC22A5, O76082 | SLC22A16, Q86VW1 |
| Substrates | verapamil, pyrilamine, tetraethylammonium, MPP+ | verapamil, tetraethylammonium, MPP+, pyrilamine | – |
| Endogenous substrates | L‐carnitine | L‐carnitine, acetyl‐L‐carnitine | L‐carnitine |
| Stoichiometry | Unknown | Unknown | Unknown |
Further Reading
Pochini L et al. (2013) OCTN cation transporters in health and disease: role as drug targets and assay development. J Biomol Screen 18: 851‐67 [PMID:23771822]
Tamai I. (2013) Pharmacological and pathophysiological roles of carnitine/organic cation transporters (OCTNs: SLC22A4, SLC22A5 and Slc22a21). Biopharm Drug Dispos 34: 29‐44 [PMID:22952014]
Organic anion transporters (OATs)
Overview
Organic anion transporters (OATs) are non‐selective transporters prominent in the kidney and intestine
| Nomenclature | Organic anion transporter 1 | Organic anion transporter 2 | Organic anion transporter 3 |
| Systematic nomenclature | SLC22A6 | SLC22A7 | SLC22A8 |
| Common abreviation | OAT1 | OAT2 | OAT3 |
| HGNC, UniProt | SLC22A6, Q4U2R8 | SLC22A7, Q9Y694 | SLC22A8, Q8TCC7 |
| Substrates | aminohippuric acid, non‐steroidal anti‐inflammatory drugs | aminohippuric acid, PGE2, non‐steroidal anti‐inflammatory drugs | estrone‐3‐sulphate [294], aminohippuric acid [294], cimetidine [294], ochratoxin A [294] |
| Stoichiometry | Unknown | Unknown | Unknown |
| Inhibitors | probenecid (Inhibition of urate transport by human SCL22A6.) (pIC50 4.9) [239] | – | – |
| Nomenclature | Organic anion transporter 7 | Organic anion transporter 5 | Organic anion transporter 4 |
| Systematic nomenclature | SLC22A9 | SLC22A10 | SLC22A11 |
| Common abreviation | OAT4 | OAT5 | – |
| HGNC, UniProt | SLC22A9, Q8IVM8 | SLC22A10, Q63ZE4 | SLC22A11, Q9NSA0 |
| Substrates | – | ochratoxin A [534] | dehydroepiandrosterone sulphate [77], estrone‐3‐sulphate [77], ochratoxin A [77] |
| Stoichiometry | Unknown | Unknown | Unknown |
Urate transporter
| Nomenclature | Urate anion exchanger 1 |
| Systematic nomenclature | SLC22A12 |
| Common abreviation | URAT1 |
| HGNC, UniProt | SLC22A12, Q96S37 |
| Endogenous substrates | uric acid [145], orotic acid [145] |
| Stoichiometry | Unknown |
| Selective inhibitors | sufinpyrazone (pIC50 4) [536] |
SLC23 family of ascorbic acid transporters
Overview
Predicted to be 12 TM segment proteins, members of this family transport the reduced form of ascorbic acid (while the oxidized form may be handled by members of the SLC2 family (GLUT1/SLC2A1, GLUT3/SLC2A3 and GLUT4/SLC2A4). Phloretin is considered a non‐selective inhibitor of these transporters, with an affinity in the micromolar range.
| Nomenclature | Sodium‐dependent vitamin C | Sodium‐dependent vitamin C | Sodium‐dependent vitamin C | Sodium‐dependent nucleobase |
| transporter 1 | transporter 2 | transporter 3 | transporter | |
| Systematic nomenclature | SLC23A1 | SLC23A2 | SLC23A3 | SLC23A4 |
| Common abreviation | SVCT1 | SVCT2 | SVCT3 | SNBT1 |
| HGNC, UniProt | SLC23A1, Q9UHI7 | SLC23A2, Q9UGH3 | SLC23A3, Q6PIS1 | SLC23A4P, – |
| Endogenous substrates | L‐ascorbic acid>D‐ascorbic acid>dehydroascorbic acid [483] | L‐ascorbic acid>D‐ascorbic acid>dehydroascorbic acid [483] | – | uracil>thymine>guanine, hypoxanthine>xanthine, uridine [526] |
| Substrates | – | – | – | 5‐fluorouracil [526] |
| Stoichiometry | 2 Na+: 1 ascorbic acid (in) [483] | 2 Na+: 1 ascorbic acid (in) [483] | – | 1 Na+ : 1 uracil (in) [526] |
| Inhibitors | phloretin (pK i 4.2) [483] | – | – | – |
| Labelled ligands | [14C]ascorbic acid (Binding) [326] | [14C]ascorbic acid | – | – |
| Comments | – | – | SLC23A3 does not transport ascorbic acid and remains an orphan transporter. | SLC23A4/SNBT1 is found in rodents and non‐human primates, but the sequence is truncated in the human genome and named as a pseudogene, SLC23A4P |
Further Reading
Bürzle M et al. (2013) The sodium‐dependent ascorbic acid transporter family SLC23. Mol. Aspects Med. 34: 436‐54 [PMID:23506882]
May JM. (2011) The SLC23 family of ascorbate transporters: ensuring that you get and keep your daily dose of vitamin C. Br. J. Pharmacol. 164: 1793‐801 [PMID:21418192]
Savini I et al. (2008) SVCT1 and SVCT2: key proteins for vitamin C uptake. Amino Acids 34: 347‐55 [PMID:17541511]
SLC24 family of sodium/potassium/calcium exchangers
Overview
The sodium/potassium/calcium exchange family of transporters utilize the extracellular sodium gradient to drive calcium and potassium co‐transport out of the cell. As is the case for NCX transporters (SLC8A family), NKCX transporters are thought to be bidirectional, with the possibility of calcium influx following depolarization of the plasma membrane. Topological modeling suggests the presence of 10 TM domains, with a large intracellular loop between the fifth and sixth TM regions.
| Nomenclature | Sodium/potassium/calcium exchanger 1 | Sodium/potassium/calcium exchanger 6 |
| Systematic nomenclature | SLC24A1 | SLC24A6 |
| Common abreviation | NKCX1 | NKCX6 |
| HGNC, UniProt | SLC24A1, O60721 | SLC8B1, Q6J4K2 |
| Stoichiometry | 4Na+:(1Ca2+ + 1K+) | – |
Comments
NKCX6 has been proposed to be the sole member of a CAX Na+/Ca2+ exchanger family, which may be the mitochondrial transporter responsible for calcium accumulation from the cytosol [441].
Further Reading
Altimimi HF et al. (2007) Na+/Ca2+‐K+ exchangers (NCKX): functional properties and physiological roles. Channels (Austin) 1: 62‐9 [PMID:18690016]
Schnetkamp PP. (2013) The SLC24 gene family of Na+/Ca2 +‐K+ exchangers: from sight and smell to memory consolidation and skin pigmentation. Mol. Aspects Med. 34: 455‐64 [PMID:23506883]
Schnetkamp PP et al. (2014) The SLC24 family of K+‐dependent Na+‐Ca2 + exchangers: structure‐function relationships. Curr Top Membr 73: 263‐87 [PMID:24745986]
Sekler I. (2015) Standing of giants shoulders the story of the mitochondrial Na(+)Ca(2+) exchanger. Biochem. Biophys. Res. Commun. 460: 50‐2 [PMID:25998733]
SLC25 family of mitochondrial transporters
Overview
Mitochondrial transporters are nuclear‐encoded proteins, which convey solutes across the inner mitochondrial membrane. Topological modelling suggests homodimeric transporters, each with six TM segments and termini in the cytosol.
Mitochondrial di‐ and tri‐carboxylic acid transporter subfamily
Overview
Mitochondrial di‐ and tri‐carboxylic acid transporters are grouped on the basis of commonality of substrates and include the citrate transporter which facilitates citric acid export from the mitochondria to allow the generation of oxalacetic acid and acetyl CoA through the action of ATP:citrate lyase.
| Nomenclature | Mitochondrial citrate | Mitochondrial dicarboxylate | Mitochondrial oxoglutarate | Mitochondrial oxodicarboxylate |
| transporter | transporter | carrier | carrier | |
| Systematic nomenclature | SLC25A1 | SLC25A10 | SLC25A11 | SLC25A21 |
| Common abreviation | CIC | DIC | OGC | ODC |
| HGNC, UniProt | SLC25A1, P53007 | SLC25A10, Q9UBX3 | SLC25A11, Q02978 | SLC25A21, Q9BQT8 |
| Substrates | phosphoenolpyruvic acid, malic acid, citric acid | SO4 2‐, phosphate, S2O3 2‐, succinic acid, malic acid | α‐ketoglutaric acid, malic acid | α‐ketoglutaric acid, α‐oxoadipic acid |
| Stoichiometry | Malate2‐ (in) : H‐citrate2‐ (out) | PO3 4‐ (in) : malate2‐ (out) | Malate2‐ (in) : oxoglutarate2‐ (out) | Oxoadipate (in) : oxoglutarate (out) |
| Inhibitors | 1,2,3‐benzenetricarboxylic acid | – | – | – |
Mitochondrial amino acid transporter subfamily
Overview
Mitochondrial amino acid transporters can be subdivided on the basis of their substrates. Mitochondrial ornithine transporters play a role in the urea cycle by exchanging cytosolic ornithine (L‐ornithine and D‐ornithine) for mitochondrial citrulline (L‐citrulline and D‐citrulline) in equimolar amounts. Further members of the family include transporters of S‐adenosylmethionine and carnitine.
| Nomenclature | AGC1 | AGC2 | Mitochondrial glutamate | Mitochondrial glutamate |
| carrier 2 | carrier 1 | |||
| Systematic nomenclature | SLC25A12 | SLC25A13 | SLC25A18 | SLC25A22 |
| Common abreviation | – | – | GC2 | GC1 |
| HGNC, UniProt | SLC25A12, O75746 | SLC25A13, Q9UJS0 | SLC25A18, Q9H1K4 | SLC25A22, Q9H936 |
| Substrates | L‐glutamic acid, 2‐amino‐3‐sulfinopropanoic acid, L‐aspartic acid | 2‐amino‐3‐sulfinopropanoic acid, L‐glutamic acid, L‐aspartic acid | L‐glutamic acid | L‐glutamic acid |
| Stoichiometry | Aspartate : glutamate H+ (bidirectional) | Aspartate : glutamate H+ (bidirectional) | Glutamate : H+ (bidirectional) | Glutamate : H+ (bidirectional) |
| Nomenclature | Mitochondrial ornithine transporter 2 | Mitochondrial ornithine transporter 1 | Carnitine/acylcarnitine carrier |
| Systematic nomenclature | SLC25A2 | SLC25A15 | SLC25A20 |
| Common abreviation | ORC2 | ORC1 | CAC |
| HGNC, UniProt | SLC25A2, Q9BXI2 | SLC25A15, Q9Y619 | SLC25A20, O43772 |
| Substrates | L‐citrulline [161], L‐arginine [161], L‐lysine [161], D‐lysine [161], D‐arginine [161], D‐citrulline [161], D‐ornithine [161], L‐ornithine [161], D‐histidine [161], L‐histidine [161] | L‐lysine [161], L‐ornithine [161], L‐citrulline [161], L‐arginine [161] | – |
| Stoichiometry | 1 Ornithine (in) :1 citrulline : 1 H+ (out) | 1 Ornithine (in) :1 citrulline : 1 H+ (out) | – |
| Comments | – | – | Exchanges cytosolic acylcarnitine for mitochondrial carnitine |
Comments
Both ornithine transporters are inhibited by the polyamine spermine[162]. Loss‐of‐function mutations in these genes are associated with hyperornithinemia‐hyperammonemia‐homocitrullinuria.
Mitochondrial phosphate transporters
Overview
Mitochondrial phosphate transporters allow the import of inorganic phosphate for ATP production.
| Nomenclature | Mitochondrial phosphate carrier |
| Systematic nomenclature | SLC25A3 |
| Common abreviation | PHC |
| HGNC, UniProt | SLC25A3, Q00325 |
| Stoichiometry | PO3 4‐ (in) : OH‐ (out) or PO3 4‐ : H+ (in) |
Mitochondrial nucleotide transporter subfamily
Overview
Mitochondrial nucleotide transporters, defined by structural similarlities, include the adenine nucleotide translocator family (SLC25A4, SLC25A5, SLC25A6 and SLC25A31), which under conditions of aerobic metabolism, allow coupling between mitochondrial oxidative phosphorylation and cytosolic energy consumption by exchanging cytosolic adenosine diphosphate for mitochondrial ATP. Further members of the mitochondrial nucleotide transporter subfamily convey diverse substrates including CoA, although not all members have had substrates identified.
| Nomenclature | Mitochondrial adenine nucleotide | Mitochondrial adenine nucleotide | Mitochondrial adenine nucleotide | Mitochondrial adenine nucleotide |
| translocator 1 | translocator 2 | translocator 3 | translocator 4 | |
| Systematic nomenclature | SLC25A4 | SLC25A5 | SLC25A6 | SLC25A31 |
| Common abreviation | ANT1 | ANT2 | ANT3 | ANT4 |
| HGNC, UniProt | SLC25A4, P12235 | SLC25A5, P05141 | SLC25A6, P12236 | SLC25A31, Q9H0C2 |
| Stoichiometry | ADP3‐ (in) : ATP4‐ (out) | ADP3‐ (in) : ATP4‐ (out) | ADP3‐ (in) : ATP4‐ (out) | ADP3‐ (in) : ATP4‐ (out) |
| Inhibitors | bongkrek acid, carboxyatractyloside | – | – | – |
| Nomenclature | Graves disease carrier | Peroxisomal membrane protein | Deoxynucleotide carrier 1 | S‐Adenosylmethionine carrier |
| Systematic nomenclature | SLC25A16 | SLC25A17 | SLC25A19 | SLC25A26 |
| Common abreviation | GDC | PMP34 | DNC | SAMC1 |
| HGNC, UniProt | SLC25A16, P16260 | SLC25A17, O43808 | SLC25A19, Q9HC21 | SLC25A26, Q70HW3 |
| Substrates | CoA and congeners | adenosine diphosphate, ATP, adenosine 5'‐monophosphate | Nucleotide Diphosphates (NDPs), Deoxynucleotide Diphosphates (dNDPs), Dideoxynucleotide Triphosphates (ddNTPs), Deoxynucleotide Triphosphates (dNTPs) | S‐adenosyl methionine |
| Stoichiometry | CoA (in) | ATP (in) | dNDP (in) : ATP (out) | – |
| Nomenclature | Mitochondrial phosphate carrier 1 | Mitochondrial phosphate carrier 2 | Mitochondrial phosphate carrier 3 |
| Systematic nomenclature | SLC25A24 | SLC25A23 | SLC25A25 |
| Common abreviation | APC1 | APC2 | APC3 |
| HGNC, UniProt | SLC25A24, Q6NUK1 | SLC25A23, Q9BV35 | SLC25A25, Q6KCM7 |
Mitochondrial uncoupling proteins
Overview
Mitochondrial uncoupling proteins allow dissipation of the mitochondrial proton gradient associated with thermogenesis and regulation of radical formation.
| Nomenclature | Uncoupling protein 1 | Uncoupling protein 2 | Uncoupling protein 3 |
| Systematic nomenclature | SLC25A7 | SLC25A8 | SLC25A9 |
| Common abreviation | UCP1 | UCP2 | UCP3 |
| HGNC, UniProt | UCP1, P25874 | UCP2, P55851 | UCP3, P55916 |
| Stoichiometry | H+ (in) | H+ (in) | H+ (in) |
| Nomenclature | Uncoupling protein 4 | Uncoupling protein 5 | KMCP1 |
| Systematic nomenclature | SLC25A27 | SLC25A14 | SLC25A30 |
| Common abreviation | UCP4 | UCP5 | – |
| HGNC, UniProt | SLC25A27, O95847 | SLC25A14, O95258 | SLC25A30, Q5SVS4 |
| Stoichiometry | H+ (in) | H+ (in) | – |
Miscellaneous SLC25 mitochondrial transporters
Overview
Many of the transporters identified below have yet to be assigned functions and are currently regarded as orphans.
Further Reading
Cioffi F et al. (2009) Uncoupling proteins: a complex journey to function discovery. Biofactors 35: 417‐28 [PMID:19626697]
Clémençon B et al. (2013) The mitochondrial ADP/ATP carrier (SLC25 family): pathological implications of its dysfunction. Mol. Aspects Med. 34: 485‐93 [PMID:23506884]
Gnoni GV et al. (2009) The mitochondrial citrate carrier: metabolic role and regulation of its activity and expression. IUBMB Life 61: 987‐94 [PMID:19787704]
Gutiérrez‐Aguilar M et al. (2013) Physiological and pathological roles of mitochondrial SLC25 carriers. Biochem. J. 454: 371‐86 [PMID:23988125]
Monné M et al. (2014) Antiporters of the mitochondrial carrier family. Curr Top Membr 73: 289‐320 [PMID:24745987]
Palmieri F. (2013) The mitochondrial transporter family SLC25: identification, properties and physiopathology. Mol. Aspects Med. 34: 465‐84 [PMID:23266187]
Palmieri F. (2014) Mitochondrial transporters of the SLC25 family and associated diseases: a review. J. Inherit. Metab. Dis. 37: 565‐75 [PMID:24797559]
Palmieri F. (2004) The mitochondrial transporter family (SLC25): physiological and pathological implications. Pflugers Arch. 447: 689‐709 [PMID:14598172]
Seifert EL et al. (2015) The mitochondrial phosphate carrier: Role in oxidative metabolism, calcium handling and mitochondrial disease. Biochem. Biophys. Res. Commun. 464: 369‐75 [PMID:26091567]
SLC26 family of anion exchangers
Overview
Along with the SLC4 family, the SLC26 family acts to allow movement of monovalent and divalent anions across cell membranes. The predicted topology is of 10‐14 TM domains with intracellular C‐ and N‐termini, probably existing as dimers. Within the family, subgroups may be identified on the basis of functional differences, which appear to function as anion exchangers and anion channels (SLC26A7 and SLC26A9).
Selective sulphate transporters
Chloride/bicarbonate exchangers
| Nomenclature | DRA | Pendrin | PAT‐1 |
| Systematic nomenclature | SLC26A3 | SLC26A4 | SLC26A6 |
| HGNC, UniProt | SLC26A3, P40879 | SLC26A4, O43511 | SLC26A6, Q9BXS9 |
| Substrates | Cl‐ | formate, HCO3 ‐, OH‐, I‐, Cl‐ | formate, oxalate, SO4 2‐, OH‐, Cl‐, HCO3 ‐, I‐ |
| Stoichiometry | 2 Cl‐ (in) : 1 HCO3 ‐ (out) or 2 Cl‐ (in) : 1 OH‐ (out) | Unknown | 1 SO4 2‐ (in) : 2 HCO3 ‐ (out) or 1 Cl‐ (in) : 2 HCO3 ‐ (out) |
Anion channels
| Nomenclature | SLC26A7 | SLC26A9 |
| HGNC, UniProt | SLC26A7, Q8TE54 | SLC26A9, Q7LBE3 |
| Substrates | NO3 ‐≫Cl‐ = Br‐ = I‐> SO4 2‐ = L‐glutamic acid | I‐> Br‐> NO3 ‐>Cl‐>L‐glutamic acid |
| Functional Characteristics | Voltage‐ and time‐independent current, linear I‐V relationship [278] | Voltage‐ and time‐independent current, linear I‐V relationship [127] |
| Comments | – | SLC26A9 has been suggested to operate in two additional modes as a Cl‐‐HCO3 ‐ exchanger and as a Na+‐anion cotransporter [79]. |
Other SLC26 anion exchangers
Further Reading
Alper SL et al. (2013) The SLC26 gene family of anion transporters and channels. Mol. Aspects Med. 34: 494‐515 [PMID:23506885]
Dorwart MR et al. (2008) The solute carrier 26 family of proteins in epithelial ion transport. Physiology (Bethesda) 23: 104‐14 [PMID:18400693]
Kato A et al. (2011) Regulation of electroneutral NaCl absorption by the small intestine. Annu. Rev. Physiol. 73: 261‐81 [PMID:21054167]
Mount DB et al. (2004) The SLC26 gene family of multifunctional anion exchangers. Pflugers Arch. 447: 710‐21 [PMID:12759755]
Nofziger C et al. (2011) Pendrin function in airway epithelia. Cell. Physiol. Biochem. 28: 571‐8 [PMID:22116372]
Ohana E et al. (2009) Diverse transport modes by the solute carrier 26 family of anion transporters. J. Physiol. (Lond.) 587: 2179‐85 [PMID:19015189]
Soleimani M. (2013) SLC26 Cl(‐)/HCO3(‐) exchangers in the kidney: roles in health and disease. Kidney Int. [PMID:23636174]
SLC27 family of fatty acid transporters
Overview
Fatty acid transporter proteins (FATPs) are a family (SLC27) of six transporters (FATP1‐6). They have at least one, and possibly six [312, 432], transmembrane segments, and are predicted on the basis of structural similarities to form dimers. SLC27 members have several structural domains: integral membrane associated domain, peripheral membrane associated domain, FATP signature, intracellular AMP binding motif, dimerization domain, lipocalin motif, and an ER localization domain (identified in FATP4 only) [153, 346, 373]. These transporters are unusual in that they appear to express intrinsic very long‐chain acyl‐CoA synthetase (EC 6.2.1.‐ , EC 6.2.1.7) enzyme activity. Within the cell, these transporters may associate with plasma and peroxisomal membranes. FATP1‐4 and ‐6 transport long‐ and very long‐chain fatty acids, while FATP5 transports long‐chain fatty acids as well as bile acids [344, 432].
| Nomenclature | Fatty acid transport protein 1 | Fatty acid transport protein 2 | Fatty acid transport protein 3 |
| Systematic nomenclature | SLC27A1 | SLC27A2 | SLC27A3 |
| Common abreviation | FATP1 | FATP2 | FATP3 |
| HGNC, UniProt | SLC27A1, Q6PCB7 | SLC27A2, O14975 | SLC27A3, Q5K4L6 |
| Endogenous substrates | palmitic acid>oleic acid>γ‐linolenic acid>octanoic acid [190]; arachidonic acid>palmitic acid>oleic acid>butyric acid [432] | – | – |
| Nomenclature | Fatty acid transport protein 4 | Fatty acid transport protein 5 | Fatty acid transport protein 6 |
| Systematic nomenclature | SLC27A4 | SLC27A5 | SLC27A6 |
| Common abreviation | FATP4 | FATP5 | FATP6 |
| HGNC, UniProt | SLC27A4, Q6P1M0 | SLC27A5, Q9Y2P5 | SLC27A6, Q9Y2P4 |
| Endogenous substrates | palmitic acid , oleic acid>γ‐linolenic acid>octanoic acid [190]; palmitic acid>oleic acid>butyric acid, γ‐linolenic acid>arachidonic acid [454] | – | palmitic acid>oleic acid>γ‐linolenic acid>octanoic acid [190] |
| Comments | FATP4 is genetically linked to restrictive dermopathy. | – | – |
Comments
Although the stoichiometry of fatty acid transport is unclear, it has been proposed to be facilitated by the coupling of fatty acid transport to conjugation with coenzyme A to form fatty acyl CoA esters. Small molecule inhibitors of FATP2 [314, 429] and FATP4 [43, 549], as well as bile acid inhibitors of FATP5 [549], have been described; analysis of the mechanism of action of some of these inhibitors suggests that transport may be selectively inhibited without altering enzymatic activity of the FATP.
C1‐BODIPY‐C12 accumulation has been used as a non‐selective index of fatty acid transporter activity.
FATP2 has two variants: Variant 1 encodes the full‐length protein, while Variant 2 encodes a shorter isoform missing an internal protein segment. FATP6 also has two variants: Variant 2 encodes the same protein as Variant 1 but has an additional segment in the 5' UTR.
Further Reading
Anderson CM et al. (2013) SLC27 fatty acid transport proteins. Mol. Aspects Med. 34: 516‐28 [PMID:23506886]
Schwenk RW et al. (2010) Fatty acid transport across the cell membrane: regulation by fatty acid transporters. Prostaglandins Leukot. Essent. Fatty Acids 82: 149‐54 [PMID:20206486]
SLC28 and SLC29 families of nucleoside transporters
Overview
Nucleoside transporters are divided into two families, the sodium‐dependent, concentrative solute carrier family 28 (SLC28) and the equilibrative, solute carrier family 29 (SLC29). The endogenous substrates are typically nucleosides, although some family members can also transport nucleobases and organic cations.
SLC28 family
Overview
SLC28 family membersappear to have 13 TM segments with cytoplasmic N‐termini and extracellular C‐termini, and function as concentrative nucleoside transporters.
| Nomenclature | Sodium/nucleoside cotransporter 1 | Sodium/nucleoside cotransporter 2 | Solute carrier family 28 member 3 |
| Systematic nomenclature | SLC28A1 | SLC28A2 | SLC28A3 |
| Common abreviation | CNT1 | CNT2 | CNT3 |
| HGNC, UniProt | SLC28A1, O00337 | SLC28A2, O43868 | SLC28A3, Q9HAS3 |
| Substrates | gemcitabine [90], zalcitabine, zidovudine | cladribine [376], didanosine, vidarabine, fludarabine [298], formycin B [298] | zalcitabine, formycin B, cladribine, 5‐fluorouridine, floxuridine, didanosine, zidovudine, zebularine, gemcitabine |
| Endogenous substrates | adenosine, uridine, cytidine, thymidine | adenosine, guanosine, inosine, thymidine | adenosine, uridine, guanosine, thymidine, inosine, cytidine |
| Stoichiometry | 1 Na+ : 1 nucleoside (in) | 1 Na+ : 1 nucleoside (in) | 2 Na+ : 1 nucleoside (in) |
Comments
A further two Na+‐dependent (stoichiometry 1 Na+: 1 nucleoside (in)) nucleoside transporters have been defined on the basis of substrate and inhibitor selectivity: CNT4 (N4/cit, which transports uridine, thymidine and guanosine) and CNT5 (N5/csg, which transports guanosine and adenosine, and may be inhibited by nitrobenzylmercaptopurine ribonucleoside).
SLC29 family
Overview
SLC29 family members appear to be composed of 11 TM segments with cytoplasmic N‐termini and extracellular C‐termini. ENT1, ENT2 and ENT4 are cell‐surface transporters, while ENT3 is intracellular, possibly lysosomal [27]. ENT1‐3 are described as broad‐spectrum equilibrative nucleoside transporters, while ENT4 is primarily a polyspecific organic cation transporter at neutral pH [231]. ENT4 transports adenosine only under acidotic conditions [31].
| Nomenclature | Equilibrative nucleoside | Equilibrative nucleoside | Equilibrative nucleoside | Plasma membrane monoamine |
| transporter 1 | transporter 2 | transporter 3 | transporter | |
| Systematic nomenclature | SLC29A1 | SLC29A2 | SLC29A3 | SLC29A4 |
| Common abreviation | ENT1 | ENT2 | ENT3 | PMAT |
| HGNC, UniProt | SLC29A1, Q99808 | SLC29A2, Q14542 | SLC29A3, Q9BZD2 | SLC29A4, Q7RTT9 |
| Endogenous substrates in order of increasing Km: | adenosine<inosine<uridine<guanosine<cytidine<hypoxanthine<adenine<thymine | – | – | – |
| Substrates | tubercidin, cytarabine, ribavirin, formycin B, cladribine, 2‐chloroadenosine, gemcitabine, didanosine, zalcitabine, pentostatin, vidarabine, floxuridine | formycin B, 2‐chloroadenosine, cytarabine, tubercidin, cladribine, gemcitabine, vidarabine, zidovudine | zidovudine [27], zalcitabine [27], didanosine [27], fludarabine [27], cordycepin [27], floxuridine [27], cladribine [27], tubercidin [27], zebularine [27] | tetraethylammonium [144], MPP+ [144] |
| Endogenous substrates | adenine [529], cytidine [529], thymidine [529], guanosine [529], thymine [529], hypoxanthine [529], uridine [529], adenosine [529], inosine [529] | adenosine, guanine, thymine, uridine, guanosine, hypoxanthine, inosine, thymidine, cytosine | adenosine [27], inosine [27], uridine [27], thymidine [27], guanosine [27], adenine [27] | histamine [144], tyramine [144], adenosine, 5‐hydroxytryptamine [144], dopamine [144] |
| Stoichiometry | Equilibrative | Equilibrative | Equilibrative | Equilibrative |
| Inhibitors | nitrobenzylmercaptopurine ribonucleoside (pK i 9.7), draflazine (pK i 9.6) [216], KF24345 (pK i 9.4) [217], NBTGR (pK i 9.3), dilazep (pK i 9), dipyridamole (pK i 8.8) [217] | – | – | decynium 22 (pK i 7) [144], rhodamine123 (pK i 6) [144], dipyridamole (pK i 5.9) [503], verapamil (pK i 4.7) [144], fluoxetine (pK i 4.6) [144], quinidine (pK i 4.6) [144], quinine (pK i 4.6) [144], desipramine (pK i 4.5) [144], cimetidine (pK i<3.3) [144] |
| Labelled ligands | [3H]nitrobenzylmercaptopurine ribonucleoside (pK d 9.3) | – | – | – |
| Comments | ENT1 has 100‐1000‐fold lower affinity for nucleobases as compared with nucleosides [529]. The affinities of draflazine, dilazep, KF24345 and dipyridamole at ENT1 transporters are species dependent, exhibiting lower affinity at rat transporters than at human transporters [217, 458]. The loss of ENT1 activity in ENT1‐null mice has been associated with a hypermineralization disorder similar to human diffuse idiopathic skeletal hyperostosis [507]. Lack of ENT1 also results in the Augustine‐null blood type [106]. | – | Defects in SLC29A3 have been implicated in Histiocytosis‐lymphadenopathy plus syndrome (OMIM:602782) and lysosomal storage diseases [233, 268]. | – |
Further Reading
Cano‐Soldado P et al. (2012) Transporters that translocate nucleosides and structural similar drugs: structural requirements for substrate recognition. Med Res Rev 32: 428‐57 [PMID:21287570]
Dos Santos‐Rodrigues A et al. (2014) Nucleoside transporters in the purinome. Neurochem. Int. 73: 229‐37 [PMID:24704797]
King AE et al. (2006) Nucleoside transporters: from scavengers to novel therapeutic targets. Trends Pharmacol. Sci. 27: 416‐25 [PMID:16820221]
Pastor‐Anglada M et al. (2008) SLC28 genes and concentrative nucleoside transporter (CNT) proteins. Xenobiotica 38: 972‐94 [PMID:18668436]
Young JD et al. (2013) The human concentrative and equilibrative nucleoside transporter families, SLC28 and SLC29. Mol. Aspects Med. 34: 529‐47 [PMID:23506887]
SLC30 zinc transporter family
Overview
Along with the SLC39 family, SLC30 transporters regulate the movement of zinc ions around the cell. In particular, these transporters remove zinc ions from the cytosol, allowing accumulation into intracellular compartments or efflux through the plasma membrane. ZnT1 is thought to be placed on the plasma membrane extruding zinc, while ZnT3 is associated with synaptic vesicles and ZnT4 and ZnT5 are linked with secretory granules. Membrane topology predictions suggest a multimeric assembly, potentially heteromultimeric [461], with subunits having six TM domains, and both termini being cytoplasmic. Dityrosine covalent linking has been suggested as a mechanism for dimerisation, particularly for ZnT3 [427]. The mechanism for zinc transport is unknown.
Comments
ZnT8/SLC30A8 is described as a type 1 diabetes susceptibility gene.
Zinc fluxes may be monitored through the use of radioisotopic Zn‐65 or the fluorescent dye FluoZin 3.
Further Reading
Bouron A et al. (2013) Contribution of calcium‐conducting channels to the transport of zinc ions. Pflugers Arch. [PMID:23719866]
Huang L et al. (2013) The SLC30 family of zinc transporters ‐ a review of current understanding of their biological and pathophysiological roles. Mol. Aspects Med. 34: 548‐60 [PMID:23506888]
Kambe T et al. (2014) Current understanding of ZIP and ZnT zinc transporters in human health and diseases. Cell. Mol. Life Sci. 71: 3281‐95 [PMID:24710731]
Kambe T et al. (2015) The Physiological, Biochemical, and Molecular Roles of Zinc Transporters in Zinc Homeostasis and Metabolism. Physiol. Rev. 95: 749‐784 [PMID:26084690]
Kawasaki E. (2012) ZnT8 and type 1 diabetes. Endocr. J. 59: 531‐7 [PMID:22447136]
Marger L et al. (2014) Zinc: an underappreciated modulatory factor of brain function. Biochem. Pharmacol. 91: 426‐35 [PMID:25130547]
Palmiter RD et al. (2004) Efflux and compartmentalization of zinc by members of the SLC30 family of solute carriers. Pflugers Arch. 447: 744‐51 [PMID:12748859]
Rungby J. (2010) Zinc, zinc transporters and diabetes. Diabetologia 53: 1549‐51 [PMID:20490449]
Wang X et al. (2010) Dietary zinc absorption: A play of Zips and ZnTs in the gut. IUBMB Life 62: 176‐82 [PMID:20120011]
SLC31 family of copper transporters
Overview
SLC31 family members, alongside the Cu‐ATPases are involved in the regulation of cellular copper levels. The CTR1 transporter is a cell‐surface transporter to allow monovalent copper accumulation into cells, while CTR2 appears to be a vacuolar/vesicular transporter [401]. Functional copper transporters appear to be trimeric with each subunit having three TM regions and an extracellular N‐terminus. CTR1 is considered to be a higher affinity copper transporter compared to CTR2. The stoichiometry of copper accumulation is unclear, but appears to be energy‐independent [304].
Comments
Copper accumulation through CTR1 is sensitive to silver ions, but not divalent cations [304].
Further Reading
Howell SB et al. (2010) Copper transporters and the cellular pharmacology of the platinum‐containing cancer drugs. Mol. Pharmacol. 77: 887‐94 [PMID:20159940]
Kim H et al. (2013) SLC31 (CTR) family of copper transporters in health and disease. Mol. Aspects Med. 34: 561‐70 [PMID:23506889]
Monné M et al. (2014) Antiporters of the mitochondrial carrier family. Curr Top Membr 73: 289‐320 [PMID:24745987]
Nose Y et al. (2006) Structure of the Ctr1 copper trans'PORE'ter reveals novel architecture. Trends Biochem. Sci. 31: 604‐7 [PMID:16982196]
Petris MJ. (2004) The SLC31 (Ctr) copper transporter family. Pflugers Arch. 447: 752‐5 [PMID:12827356]
Zheng W et al. (2012) Regulation of brain iron and copper homeostasis by brain barrier systems: implication in neurodegenerative diseases. Pharmacol. Ther. 133: 177‐88 [PMID:22115751]
SLC32 vesicular inhibitory amino acid transporter
Overview
The vesicular inhibitory amino acid transporter, VIAAT (also termed the vesicular GABA transporter VGAT), which is the sole representative of the SLC32 family, transports GABA, or glycine, into synaptic vesicles [182, 183], and is a member of the structurally‐defined amino acid‐polyamine‐organocation/APC clan composed of SLC32, SLC36 and SLC38 transporter families (see [435]). VIAAT was originally suggested to be composed of 10 TM segments with cytoplasmic N‐ and C‐termini [335]. However, an alternative 9TM structure with the N terminus facing the cytoplasm and the C terminus residing in the synaptic vesicle lumen has subsequently been reported [333]. VIAAT acts as an antiporter for inhibitory amino acids and protons. The accumulation of GABA and glycine within vesicles is driven by both the chemical (ΔpH) and electrical (Δ ψ) components of the proton electrochemical gradient (Δ μ H+) established by a vacuolar H+‐ATPase [335]. However, one study, [259], presented evidence that VIAAT is instead a Cl‐/GABA co‐transporter. VIAAT co‐exists with VGLUT1(SLC17A7), or VGLUT2(SLC17A6), in the synaptic vesicles of selected nerve terminals [155, 539]. VIAAT knock out mice die between embryonic day 18.5 and birth [515]. In cultures of spinal cord neurones established from earlier embryos, the co‐release of of GABA and glycine from synaptic vesicles is drastically reduced, providing direct evidence for the role of VIAAT in the sequestration of both transmitters [425, 515].
| Nomenclature | Vesicular inhibitory amino acid transporter |
| Systematic nomenclature | SLC32A1 |
| Common abreviation | VIAAT |
| HGNC, UniProt | SLC32A1, Q9H598 |
| Endogenous substrates | β‐alanine, γ‐hydroxybutyric acid, GABA (K m5 × 10−3M) [335], glycine |
| Stoichiometry | 1 amino acid (in): 1 H+ (out) [182] or 1 amino acid: 2Cl‐ (in) [259] |
| Inhibitors | vigabatrin (pIC50 2.1) [335] |
Further Reading
Erickson JD et al. (2006) Activity‐dependent regulation of vesicular glutamate and GABA transporters: a means to scale quantal size. Neurochem. Int. 48: 643‐9 [PMID:16546297]
Gasnier B. (2000) The loading of neurotransmitters into synaptic vesicles. Biochimie 82: 327‐37 [PMID:10865121]
Gasnier B. (2004) The SLC32 transporter, a key protein for the synaptic release of inhibitory amino acids. Pflugers Arch. 447: 756‐9 [PMID:12750892]
Schiöth HB et al. (2013) Evolutionary origin of amino acid transporter families SLC32, SLC36 and SLC38 and physiological, pathological and therapeutic aspects. Mol. Aspects Med. 34: 571‐85 [PMID:23506890]
SLC33 acetylCoA transporter
Overview
Acetylation of proteins is a post‐translational modification mediated by specific acetyltransferases, using the donor acetyl CoA. SLC33A1/AT1 is a putative 11 TM transporter present on the endoplasmic reticulum, expressed in all tissues, but particularly abundant in the pancreas [267], which imports cytosolic acetyl CoA into these intracellular organelles.
| Nomenclature | AcetylCoA transporter |
| Systematic nomenclature | SLC33A1 |
| Common abreviation | ACATN1 |
| HGNC, UniProt | SLC33A1, O00400 |
| Endogenous substrates | acetyl CoA |
| Stoichiometry | Unknown |
| Labelled ligands | [14C]acetylCoA (Binding) |
Comments
In heterologous expression studies, acetyl CoA transport through AT1 was inhibited by coenzyme A, but not acetic acid, ATP or UDP‐galactose[255]. A loss‐of‐function mutation in ACATN1/SLC33A1 has been associated with spastic paraplegia (SPG42, [317]), although this observation could not be replicated in a subsequent study [436].
Further Reading
Hirabayashi Y et al. (2004) The acetyl‐CoA transporter family SLC33. Pflugers Arch. 447: 760‐2 [PMID:12739170]
Hirabayashi Y et al. (2013) The acetyl‐CoA transporter family SLC33. Mol. Aspects Med. 34: 586‐9 [PMID:23506891]
SLC34 family of sodium phosphate co‐transporters
Overview
The SLC34 family are sometimes referred to as Type II sodium‐phosphate co‐transporters, alongside Type I (SLC17 family) and Type III (SLC20 family) transporters. Topological modelling suggests eight TM domains with C‐ and N‐ termini in the cytoplasm, and a re‐entrant loop at TM7/8. SLC34 family members are expressed on the apical surfaces of epithelia in the intestine and kidneys to regulate body phosphate levels, principally NaPi‐IIa and NaPi‐IIb, respectively. NaPi‐IIa and NaPi‐IIb are electrogenic, while NaPiIIc is electroneutral [10].
| Nomenclature | Sodium phosphate 1 | Sodium phosphate 2 | Sodium phosphate 3 |
| Systematic nomenclature | SLC34A1 | SLC34A2 | SLC34A3 |
| Common abreviation | NaPi‐IIa | NaPi‐IIb | NaPi‐IIc |
| HGNC, UniProt | SLC34A1, Q06495 | SLC34A2, O95436 | SLC34A3, Q8N130 |
| Stoichiometry | 3 Na+ : 1 HPO4 2‐ (in) [168] | 3 Na+ : 1 HPO4 2‐(in) [10] | 2 Na+ : 1 HPO4 2‐ (in) [10] |
| Antibodies | – | lifastuzumab vedotin (Binding) [115] | – |
Comments
These transporters can be inhibited by foscarnet, in contrast to type III sodium‐phosphate cotransporters, the SLC20 family.
Further Reading
Biber J et al. (2013) Phosphate transporters and their function. Annu. Rev. Physiol. 75: 535‐50 [PMID:23398154]
Forster IC et al. (2013) Phosphate transporters of the SLC20 and SLC34 families. Mol. Aspects Med. 34: 386‐95 [PMID:23506879]
Marks J et al. (2010) Phosphate homeostasis and the renal‐gastrointestinal axis. Am. J. Physiol. Renal Physiol. 299: F285‐96 [PMID:20534868]
Miyamoto K et al. (2011) Sodium‐dependent phosphate cotransporters: lessons from gene knockout and mutation studies. J Pharm Sci 100: 3719‐30 [PMID:21567407]
Murer H et al. (2004) The sodium phosphate cotransporter family SLC34. Pflugers Arch. 447: 763‐7 [PMID:12750889]
Shobeiri N et al. (2013) Phosphate: an old bone molecule but new cardiovascular risk factor. Br J Clin Pharmacol [PMID:23506202]
Wagner CA et al. (2014) The SLC34 family of sodium‐dependent phosphate transporters. Pflugers Arch. 466: 139‐53 [PMID:24352629]
SLC35 family of nucleotide sugar transporters
Overview
Glycoprotein formation in the Golgi and endoplasmic reticulum relies on the accumulation of nucleotide‐conjugated sugars via the SLC35 family of transporters. These transporters have a predicted topology of 10 TM domains, with cytoplasmic termini, and function as exchangers, swopping nucleoside monophosphates for the corresponding nucleoside diphosphate conjugated sugar. Five subfamilies of transporters have been identified on the basis of sequence similarity, namely SLC35A1, SLC35A2, SLC35A3, SLC35A4 and SLC35A5; SLC35B1, SLC35B2, SLC35B3 and SLC35B4; SLC35C1 and SLC35C2; SLC35D1, SL35D1, SLC35D2 and SLC35D3, and the subfamily of orphan SLC35 transporters, SLC35E1‐4 and SLC35F1‐5.
| Nomenclature | CMP‐sialic acid transporter | UDP‐galactose transporter | UDP‐N‐acetylglucosamine | PAPS transporter 1 | PAPS transporter 2 |
| transporter | |||||
| Systematic nomenclature | SLC35A1 | SLC35A2 | SLC35A3 | SLC35B2 | SLC35B3 |
| HGNC, UniProt | SLC35A1, P78382 | SLC35A2, P78381 | SLC35A3, Q9Y2D2 | SLC35B2, Q8TB61 | SLC35B3, Q9H1N7 |
| Substrates | CMP‐sialic acid [243] | UDP‐galactose [245, 348], UDP N‐acetyl‐glucosamine [245, 348] | UDP N‐acetyl‐glucosamine [246] | A3P5PS [262] | A3P5PS [261] |
| Nomenclature | YEA | GDP‐Fucose transporter | UDP‐glucuronic | HFRC1 |
| acid/UDP-N-acetylgalactosamine | ||||
| dual transporter | ||||
| Systematic nomenclature | SLC35B4 | SLC35C1 | SLC35D1 | SLC35D2 |
| HGNC, UniProt | SLC35B4, Q969S0 | SLC35C1, Q96A29 | SLC35D1, Q9NTN3 | SLC35D2, Q76EJ3 |
| Substrates | UDP‐xylose [18], UDP N‐acetyl‐glucosamine [18] | GDP‐fucose [325] | UDP‐N‐acetylgalactosamine [354], UDP‐glucuronic acid [354] | UDP‐N‐acetylgalactosamine [244] |
Further Reading
Ishida N et al. (2004) Molecular physiology and pathology of the nucleotide sugar transporter family (SLC35). Pflugers Arch. 447: 768‐75 [PMID:12759756]
Song Z. (2013) Roles of the nucleotide sugar transporters (SLC35 family) in health and disease. Mol. Aspects Med. 34: 590‐600 [PMID:23506892]
SLC36 family of proton‐coupled amino acid transporters
Overview
The SLC36 family of proton‐coupled amino acid transporters (or PAT) is highly expressed in the intestine and kidney, having roles in the disposition of amino acids [474]. PAT1 is found on the gut epithelia luminal surface accumulating dietary amino acids, and additionally in lysosomal membranes where it likely functions as an efflux mechanism for amino acids produced during intralysosomal proteolysis [4, 420]. PAT2 is found at the apical membrane of the kidney proximal tubule [66]. PAT1 and PAT2 are predicted to have 11 TM domains with intracellular N‐termini [48, 420].
Comments
Both PAT1 and PAT2 can also function as an electroneutral transport system for H+ and fatty acids including acetic acid, propanoic acid and butyric acid[164].
Loss‐of‐function mutations in PAT2 lead to iminoglycinuria and hyperglycinuria in man [65].
Further Reading
Boll M et al. (2004) The SLC36 family: proton‐coupled transporters for the absorption of selected amino acids from extracellular and intracellular proteolysis. Pflugers Arch. 447: 776‐9 [PMID:12748860]
Schiöth HB et al. (2013) Evolutionary origin of amino acid transporter families SLC32, SLC36 and SLC38 and physiological, pathological and therapeutic aspects. Mol. Aspects Med. 34: 571‐85 [PMID:23506890]
Thwaites DT et al. (2011) The SLC36 family of proton‐coupled amino acid transporters and their potential role in drug transport. Br. J. Pharmacol. 164: 1802‐16 [PMID:21501141]
Thwaites DT et al. (2007) Deciphering the mechanisms of intestinal imino (and amino) acid transport: the redemption of SLC36A1. Biochim. Biophys. Acta 1768: 179‐97 [PMID:17123464]
SLC37 family of phosphosugar/phosphate exchangers
Overview
The family of sugar‐phosphate exchangers pass particular phosphorylated sugars across intracellular membranes, exchanging for inorganic phosphate. Of the family of sugar phosphate transporters, most information is available on SPX4, the glucose‐6‐phosphate transporter. This is a 10 TM domain protein with cytoplasmic termini and is associated with the endoplasmic reticulum, with tissue‐specific splice variation.
| Nomenclature | Glycerol‐3‐phosphate transporter | Sugar phosphate exchanger 2 | Glucose‐6‐phosphate transporter |
| Systematic nomenclature | SLC37A1 | SLC37A2 | SLC37A4 |
| Common abreviation | SPX1 | SPX2 | SPX4 |
| HGNC, UniProt | SLC37A1, P57057 | SLC37A2, Q8TED4 | SLC37A4, O43826 |
| Endogenous substrates | glycerol 3‐phosphate, glucose 6‐phosphate | glucose 6‐phosphate | glucose 6‐phosphate |
| Stoichiometry | Glucose 6‐phosphate (in): phosphate (out) [379]. | Glucose 6‐phosphate (in): phosphate (out) [379]. | Glucose 6‐phosphate (in): phosphate (out) [84]. |
| Comments | – | – | Multiple polymorphisms have been described for the SLC37A4 gene, some of which associate with a glycogen storage disease [6]. |
Further Reading
Bartoloni L et al. (2004) The human sugar‐phosphate/phosphate exchanger family SLC37. Pflugers Arch. 447: 780‐3 [PMID:12811562]
Chou JY et al. (2014) The SLC37 family of sugar‐phosphate/phosphate exchangers. Curr Top Membr 73: 357‐82 [PMID:24745989]
Chou JY et al. (2013) The SLC37 family of phosphate‐linked sugar phosphate antiporters. Mol. Aspects Med. 34: 601‐11 [PMID:23506893]
SLC38 family of sodium‐dependent neutral amino acid transporters
Overview
The SLC38 family of transporters appears to be responsible for the functionally‐defined system A and system N mechanisms of amino acid transport and are mostly expressed in the CNS. Two distinct subfamilies are identifiable within the SLC38 transporters. SNAT1, SNAT2 and SNAT4 appear to resemble system A transporters in accumulating neutral amino acids under the influence of the sodium gradient. SNAT3 and SNAT5 appear to resemble system N transporters in utilizing proton co‐transport to accumulate amino acids. The predicted membrane topology is of 11 TM domains with an extracellular C‐terminus and intracellular N‐terminus [435].
System A‐like transporters
System N‐like transporters
| Nomenclature | Sodium‐coupled neutral amino acid transporter 3 | Sodium‐coupled neutral amino acid transporter 5 |
| Systematic nomenclature | SLC38A3 | SLC38A5 |
| Common abreviation | SNAT3 | SNAT5 |
| HGNC, UniProt | SLC38A3, Q99624 | SLC38A5, Q8WUX1 |
| Substrates | L‐histidine , L‐glutamine>L‐asparagine, L‐alanine>L‐glutamic acid [157] | L‐asparagine, L‐serine, L‐histidine, L‐glutamine>glycine, L‐alanine [359] |
| Substrates | MeAIB | MeAIB |
| Stoichiometry | 1 Na+ : 1 amino acid (in) : 1 H+ (out) [59] | 1 Na+ : 1 amino acid (in) : 1 H+ (out) [359] |
| Labelled ligands | [14C]glutamine, [3H]glutamine | [14C]histidine, [3H]histidine |
Orphan SLC38 transporters
| Nomenclature | Putative sodium‐coupled neutral amino acid transporter 7 |
| Systematic nomenclature | SLC38A7 |
| Common abreviation | SNAT7 |
| HGNC, UniProt | SLC38A7, Q9NVC3 |
| Comments | SNAT7/SLC38A7 has been described to be a system N‐like transporter allowing preferential accumulation of glutamine (e.g. L‐glutamine), histidine (e.g. L‐histidine) and asparagine (e.g. L‐asparagine) [237]. |
Further Reading
Bröer S. (2014) The SLC38 family of sodium‐amino acid co‐transporters. Pflugers Arch. 466: 155‐72 [PMID:24193407]
Bröer S et al. (2011) The role of amino acid transporters in inherited and acquired diseases. Biochem. J. 436: 193‐211 [PMID:21568940]
Hägglund MG et al. (2011) Identification of SLC38A7 (SNAT7) protein as a glutamine transporter expressed in neurons. J. Biol. Chem. 286: 20500‐11 [PMID:21511949]
Mackenzie B et al. (2004) Sodium‐coupled neutral amino acid (System N/A) transporters of the SLC38 gene family. Pflugers Arch. 447: 784‐95 [PMID:12845534]
Schiöth HB et al. (2013) Evolutionary origin of amino acid transporter families SLC32, SLC36 and SLC38 and physiological, pathological and therapeutic aspects. Mol. Aspects Med. 34: 571‐85 [PMID:23506890]
Sundberg BE et al. (2008) The evolutionary history and tissue mapping of amino acid transporters belonging to solute carrier families SLC32, SLC36, and SLC38. J. Mol. Neurosci. 35: 179‐93 [PMID:18418736]
SLC39 family of metal ion transporters
Overview
Along with the SLC30 family, SLC39 family members regulate zinc movement in cells. SLC39 metal ion transporters accumulate zinc into the cytosol. Membrane topology modelling suggests the presence of eight TM regions with both termini extracellular or in the lumen of intracellular organelles. The mechanism for zinc transport for many members is unknown but appears to involve co‐transport of bicarbonate ions [191, 321].
Comments
Zinc fluxes may be monitored through the use of radioisotopic Zn‐65 or the fluorescent dye FluoZin 3.
The bicarbonate transport inhibitor DIDS has been reported to inhibit cation accumulation through ZIP14 [191].
Further Reading
Eide DJ. (2004) The SLC39 family of metal ion transporters. Pflugers Arch. 447: 796‐800 [PMID:12748861]
Franz MC et al. (2013) Zinc transporters in prostate cancer. Mol. Aspects Med. 34: 735‐41 [PMID:23506906]
Himeno S et al. (2009) The role of zinc transporters in cadmium and manganese transport in mammalian cells. Biochimie 91: 1218‐22 [PMID:19375483]
Jeong J et al. (2013) The SLC39 family of zinc transporters. Mol. Aspects Med. 34: 612‐9 [PMID:23506894]
Kambe T et al. (2014) Current understanding of ZIP and ZnT zinc transporters in human health and diseases. Cell. Mol. Life Sci. 71: 3281‐95 [PMID:24710731]
Kambe T et al. (2015) The Physiological, Biochemical, and Molecular Roles of Zinc Transporters in Zinc Homeostasis and Metabolism. Physiol. Rev. 95: 749‐784 [PMID:26084690]
Marger L et al. (2014) Zinc: an underappreciated modulatory factor of brain function. Biochem. Pharmacol. 91: 426‐35 [PMID:25130547]
Rungby J. (2010) Zinc, zinc transporters and diabetes. Diabetologia 53: 1549‐51 [PMID:20490449]
Thévenod F. (2010) Catch me if you can! Novel aspects of cadmium transport in mammalian cells. Biometals 23: 857‐75 [PMID:20204475]
SLC40 iron transporter
Overview
Alongside the SLC11 family of proton‐coupled metal transporters, ferroportin allows the accumulation of iron from the diet. Whilst SLC11A2 functions on the apical membrane, ferroportin acts on the basolateral side of the enterocyte, as well as regulating macrophage and placental iron levels. The predicted topology is of 12 TM domains, with intracellular termini [407], with the functional transporter potentially a dimeric arrangement [3, 111]. Ferroportin is essential for iron homeostasis [126]. Ferroportin is expressed on the surface of cells that store and transport iron, such as duodenal enterocytes, hepatocytes, adipocytes and reticuloendothelial macrophages. Levels of ferroportin are regulated by its association with (binding to) hepcidin, a 25 amino acid hormone responsive to circulating iron levels (amongst other signals). Hepcidin binding targets ferroportin for internalisation and degradation, lowering the levels of iron export to the blood. Novel therapeutic agents which stabilise ferroportin or protect it from hepcidin‐induced degradation are being developed as anti‐anemia agents. Anti‐ferroportin monoclonal antibodies are such an agent.
| Nomenclature | Ferroportin |
| Systematic nomenclature | SLC40A1 |
| Common abreviation | IREG1 |
| HGNC, UniProt | SLC40A1, Q9NP59 |
| Endogenous substrates | Fe2+ |
| Stoichiometry | Unknown |
| Antibodies | LY2928057 (Binding) [311] |
Comments
Hepcidin (HAMP, P81172), cleaved into hepcidin‐25(HAMP, P81172) and hepcidin‐20(HAMP, P81173), is a small protein that increases upon inflammation, binds to ferroportin to regulate its cellular distribution and degradation. Gene disruption in mice results in embryonic lethality [126], while loss‐of‐function mutations in man are associated with haemochromatosis [112].
Further Reading
McKie AT et al. (2004) The SLC40 basolateral iron transporter family (IREG1/ferroportin/MTP1). Pflugers Arch. 447: 801‐6 [PMID:12836025]
Montalbetti N et al. (2013) Mammalian iron transporters: families SLC11 and SLC40. Mol. Aspects Med. 34: 270‐87 [PMID:23506870]
SLC41 family of divalent cation transporters
Overview
By analogy with bacterial orthologues, this family is probably magnesium transporters. The prokaryote orthologue, MgtE, is responsible for uptake of divalent cations, while the heterologous expression studies of mammalian proteins suggest Mg2+ efflux [287], possibly as a result of co‐expression of particular protein partners (see [421]). Topological modelling suggests 10 TM domains with cytoplasmic C‐ and N‐ termini.
| Nomenclature | Solute carrier family 41 member 1 | Solute carrier family 41 member 2 |
| Systematic nomenclature | SLC41A1 | SLC41A2 |
| Common abreviation | MgtE | – |
| HGNC, UniProt | SLC41A1, Q8IVJ1 | SLC41A2, Q96JW4 |
| Substrates | Co2+ [201], Cu2+ [201], Ba2+ [201], Cd2+ [201], Zn2+ [201], Mg2+ [201], Sr2+ [201], Fe2+ [201] | Ba2+ [200], Mg2+ [200], Co2+ [200], Ni2+ [200], Mn2+ [200], Fe2+ [200] |
| Stoichiometry | Unknown | Unknown |
Further Reading
Moomaw AS et al. (2008) The unique nature of mg2+ channels. Physiology (Bethesda) 23: 275‐85 [PMID:18927203]
Payandeh J et al. (2013) The structure and regulation of magnesium selective ion channels. Biochim. Biophys. Acta [PMID:23954807]
Quamme GA. (2010) Molecular identification of ancient and modern mammalian magnesium transporters. Am. J. Physiol., Cell Physiol. 298: C407‐29 [PMID:19940067]
Sahni J et al. (2013) The SLC41 family of MgtE‐like magnesium transporters. Mol. Aspects Med. 34: 620‐8 [PMID:23506895]
Schweigel‐Röntgen M et al. (2014) SLC41 transporters–molecular identification and functional role. Curr Top Membr 73: 383‐410 [PMID:24745990]
SLC42 family of Rhesus glycoprotein ammonium transporters
Overview
Rhesus is commonly defined as a ‘factor’ that determines, in part, blood type, and whether neonates suffer from haemolytic disease of the newborn. These glycoprotein antigens derive from two genes, RHCE (P18577) and RHD(Q02161), expressed on the surface of erythrocytes. On erythrocytes, RhAG associates with these antigens and functions as an ammonium transporter. RhBG and RhBG are non‐erythroid related sequences associated with epithelia. Topological modelling suggests the presence of 12TM with cytoplasmic N‐ and C‐ termini. The majority of information on these transporters derives from orthologues in yeast, plants and bacteria. More recent evidence points to family members being permeable to carbon dioxide, leading to the term gas channels.
| Nomenclature | Ammonium transporter Rh type A | Ammonium transporter Rh type B | Ammonium transporter Rh type C |
| Systematic nomenclature | SLC42A1 | SLC42A2 | SLC42A3 |
| Common abreviation | RhAG | RhBG | RhCG |
| HGNC, UniProt | RHAG, Q02094 | RHBG, Q9H310 | RHCG, Q9UBD6 |
| Substrates | NH4 + [510], NH3 [408], CO2 [143] | – | NH3 [552] |
| Stoichiometry | Unknown | Unknown | Unknown |
| Labelled ligands | [14C]methylamine (Binding) [228] | – | [14C]methylamine (Binding) [330] – Mouse |
Further Reading
Huang CH et al. (2010) The Rh protein family: gene evolution, membrane biology, and disease association. Cell. Mol. Life Sci. 67: 1203‐18 [PMID:19953292]
Nakhoul NL et al. (2004) Non‐erythroid Rh glycoproteins: a putative new family of mammalian ammonium transporters. Pflugers Arch. 447: 807‐12 [PMID:12920597]
Nakhoul NL et al. (2013) Characteristics of mammalian Rh glycoproteins (SLC42 transporters) and their role in acid‐base transport. Mol. Aspects Med. 34: 629‐37 [PMID:23506896]
Weiner ID et al. (2011) Role of NH3 and NH4+ transporters in renal acid‐base transport. Am. J. Physiol. Renal Physiol. 300: F11‐23 [PMID:21048022]
Weiner ID et al. (2014) Ammonia transport in the kidney by Rhesus glycoproteins. Am. J. Physiol. Renal Physiol. 306: F1107‐20 [PMID:24647713]
SLC43 family of large neutral amino acid transporters
Overview
LAT3 (SLC43A1) and LAT4 (SLC43A2) are transporters with system L amino acid transporter activity, along with the structurally and functionally distinct transporters LAT1 and LAT2 that are members of the SLC7 family. LAT3 and LAT4 contain 12 putative TM domains with both N and C termini located intracellularly. They transport neutral amino acids in a manner independent of Na+ and Cl‐ and with two kinetic components [22, 47]. LAT3/SLC43A1 is expressed in human tissues at high levels in the pancreas, liver, skeletal muscle and fetal liver [22] whereas LAT4/SLC43A2 is primarily expressed in the placenta, kidney and peripheral blood leukocytes [47]. SLC43A3 is expressed in vascular endothelial cells [502] but remains to be characterised.
| Nomenclature | L‐type amino acid transporter 3 | L‐type amino acid transporter 4 |
| Systematic nomenclature | SLC43A1 | SLC43A2 |
| Common abreviation | LAT3 | LAT4 |
| HGNC, UniProt | SLC43A1, O75387 | SLC43A2, Q8N370 |
| Substrates | L‐isoleucine [22], L‐valinol [22], L‐leucinol [22], L‐phenylalaninol [22], L‐leucine [22], L‐phenylalanine [22], L‐valine [22], L‐methionine [22] | L‐isoleucine, L‐valinol, L‐leucinol, L‐leucine, L‐phenylalanine, L‐valine, L‐methionine |
| Stoichiometry | Operates by facilitative diffusion | Operates by facilitative diffusion |
Comments
Covalent modification of LAT3 by N‐ethylmaleimide inhibits its function [22] and at LAT4 inhibits the low‐, but not high‐affinity component of transport [47].
Further Reading
Bodoy S et al. (2013) The small SLC43 family: facilitator system l amino acid transporters and the orphan EEG1. Mol. Aspects Med. 34: 638‐45 [PMID:23268354]
SLC44 choline transporter‐like family
Overview
Members of the choline transporter‐like family are encoded by five genes (CTL1‐CTL5) with further diversity occurring through alternative splicing of CTL1, 4 and 5 [477]. CTL family members are putative 10TM domain proteins with extracellular termini that mediate Na+‐independent transport of choline with an affinity that is intermediate to that of the high affinity choline transporter CHT1 (SLC5A7) and the low affinity organic‐cation transporters [OCT1 (SLC22A1) and OCT2 (SLC22A2)] [343]. CLT1 is expressed almost ubiquitously in human tissues [514] and mediates choline transport across the plasma and mitochondrial membranes [342]. Transport of choline by CTL2, which in rodents is expressed as two isoforms (CTL2P1 and CLTP2; [288]) in lung, colon, inner ear and spleen and to a lesser extent in brain, tongue, liver, and kidney, has only recently been demonstrated [288, 358]. CTL3‐5 remain to be characterized functionally.
| Nomenclature | Choline transporter‐like 1 |
| Systematic nomenclature | SLC44A1 |
| Common abreviation | CTL1 |
| HGNC, UniProt | SLC44A1, Q8WWI5 |
| Substrates | choline |
| Stoichiometry | Unknown: uptake enhanced in the absence of extracellular Na+, reduced by membrane depolarization, extracellular acidification and collapse of plasma membrane H+ electrochemical gradient |
| Inhibitors | hemicholinium‐3 (pK i 3.5–4.5) |
Comments
Data tabulated are features observed for CLT1 endogenous to: rat astrocytes [242]; rat renal tubule epithelial cells [524]; human colon carcinoma cells [289]; human keratinocytes [486] and human neuroblastoma cells [525]. Choline uptake by CLT1 is inhibited by numerous organic cations (e.g. [242, 524, 525]). In the guinea‐pig, CTL2 is a target for antibody‐induced hearing loss [355] and in man, a polymorphism in CTL2 constitutes the human neutrophil alloantigen‐3a (HNA‐3a; [203]).
Further Reading
Inazu M. (2014) Choline transporter‐like proteins CTLs/SLC44 family as a novel molecular target for cancer therapy. Biopharm Drug Dispos 35: 431‐49 [PMID:24532461]
Lockman PR et al. (2002) The transport of choline. Drug Dev Ind Pharm 28: 749‐71 [PMID:12236062]
Michel V et al. (2006) Choline transport for phospholipid synthesis. Exp. Biol. Med. (Maywood) 231: 490‐504 [PMID:16636297]
Traiffort E et al. (2013) The choline transporter‐like family SLC44: properties and roles in human diseases. Mol. Aspects Med. 34: 646‐54 [PMID:23506897]
SLC45 family of putative sugar transporters
Overview
Members of the SLC45 family remain to be fully characterised. SLC45A1 was initially identified in the rat brain, particularly predominant in the hindbrain, as a proton‐associated sugar transport, induced by hypercapnia [447]. The protein is predicted to have 12TM domains, with intracellular termini. The SLC45A2 gene is thought to encode a transporter protein that mediates melanin synthesis. Mutations in SLC45A2 are a cause of oculocutaneous albinism type 4 (e.g. [361]), and polymorphisms in this gene are associated with variations in skin and hair color (e.g. [202]).
Further Reading
Bartölke R et al. (2014) Proton‐associated sucrose transport of mammalian solute carrier family 45: an analysis in Saccharomyces cerevisiae. Biochem. J. 464: 193‐201 [PMID:25164149]
Vitavska O et al. (2013) The SLC45 gene family of putative sugar transporters. Mol. Aspects Med. 34: 655‐60 [PMID:23506898]
SLC46 family of folate transporters
Overview
Based on the proptypical member of this family, PCFT, this family includes proton‐driven transporters with 11 TM segments. SLC46A1 has been described to act as an intestinal proton‐coupled high‐affinity folic acid transporter [393], with lower affinity for heme. Folic acid accumulation is independent of Na+ or K+ ion concentrations, but driven by extracellular protons with an as yet undefined stoichiometry.
| Nomenclature | Proton‐coupled folate transporter |
| Systematic nomenclature | SLC46A1 |
| Common abreviation | PCFT |
| HGNC, UniProt | SLC46A1, Q96NT5 |
| Substrates | folic acid (1.3μM) >heme (>100 μM) [356] |
| Substrates | pemetrexed, N‐formyltetrahydrofolate, methotrexate [393] |
| Endogenous substrates | N5‐methyltetrafolate [393] |
| Labelled ligands | [3H]N5‐methylfolate (Binding), [3H]folic acid, [3H]folinic acid (Binding), [3H]methotrexate, [3H]pemetrexed (Binding) |
| Comments | Loss‐of‐function mutations in PCFT (SLC46A1) are the molecular basis for hereditary folate maladsorption [428]. |
Further Reading
Anderson CM et al. (2010) Hijacking solute carriers for proton‐coupled drug transport. Physiology (Bethesda) 25: 364‐77 [PMID:21186281]
Desmoulin SK et al. (2012) The human proton‐coupled folate transporter: Biology and therapeutic applications to cancer. Cancer Biol. Ther. 13: 1355‐73 [PMID:22954694]
Hou Z et al. (2014) Biology of the major facilitative folate transporters SLC19A1 and SLC46A1. Curr Top Membr 73: 175‐204 [PMID:24745983]
Matherly LH et al. (2014) The major facilitative folate transporters solute carrier 19A1 and solute carrier 46A1: biology and role in antifolate chemotherapy of cancer. Drug Metab. Dispos. 42: 632‐49 [PMID:24396145]
Thwaites DT et al. (2007) H+‐coupled nutrient, micronutrient and drug transporters in the mammalian small intestine. Exp. Physiol. 92: 603‐19 [PMID:17468205]
Wilson MR et al. (2015) Structural determinants of human proton‐coupled folate transporter oligomerization: role of GXXXG motifs and identification of oligomeric interfaces at transmembrane domains 3 and 6. Biochem. J. [PMID:25877470]
Zhao R et al. (2011) Mechanisms of membrane transport of folates into cells and across epithelia. Annu. Rev. Nutr. 31: 177‐201 [PMID:21568705]
Zhao R et al. (2013) Folate and thiamine transporters mediated by facilitative carriers (SLC19A1‐3 and SLC46A1) and folate receptors. Mol. Aspects Med. 34: 373‐85 [PMID:23506878]
SLC47 family of multidrug and toxin extrusion transporters
Overview
These proton:organic cation exchangers are predicted to have 13 TM segments [545] and are suggested to be responsible for excretion of many drugs in the liver and kidneys.
| Nomenclature | Multidrug and toxin extrusion | MATE2 |
| Systematic nomenclature | SLC47A1 | SLC47A2 |
| Common abreviation | MATE1 | MATE2‐K |
| HGNC, UniProt | SLC47A1, Q96FL8 | SLC47A2, Q86VL8 |
| Substrates | quinidine [467], cephradine [467], metformin (K m7.8 × 10−4M) [467], cephalexin [467], cimetidine (K m1.7 × 10−4M) [369, 467], paraquat [85] | guanidine [467], procainamide [334], metformin (K m1.9 × 10−3M) [334, 467], aciclovir [467], MPP+ [334], cimetidine (K m1.2 × 10−4M) [334, 467], N1‐methylnicotinamide [334] |
| Endogenous substrates | thiamine [467], creatine [467] | creatine [467], thiamine [467] |
| (Sub)family‐selective inhibitors | pyrimethamine (pK i 7.1) [249], cimetidine (pK i 6) [482] | pyrimethamine (pK i 6.3) [249] – Mouse, cimetidine (pK i 5.1) [482] |
| Labelled ligands | [14C]TEA [374, 469], [14C]metformin [467, 469] | [14C]TEA [467] |
Comments
DAPI has been used to allow quantification of MATE1 and MATE2‐mediated transport activity [531]. MATE2 and MATE2‐B are inactive splice variants of MATE2‐K [334].
Further Reading
Damme K et al. (2011) Mammalian MATE (SLC47A) transport proteins: impact on efflux of endogenous substrates and xenobiotics. Drug Metab. Rev. 43: 499‐523 [PMID:21923552]
Motohashi H et al. (2013) Multidrug and toxin extrusion family SLC47: physiological, pharmacokinetic and toxicokinetic importance of MATE1 and MATE2‐K. Mol. Aspects Med. 34: 661‐8 [PMID:23506899]
Terada T et al. (2008) Physiological and pharmacokinetic roles of H+/organic cation antiporters (MATE/SLC47A). Biochem. Pharmacol. 75: 1689‐96 [PMID:18262170]
Yonezawa A et al. (2011) Importance of the multidrug and toxin extrusion MATE/SLC47A family to pharmacokinetics, pharmacodynamics/toxicodynamics and pharmacogenomics. Br. J. Pharmacol. 164: 1817‐25 [PMID:21457222]
SLC48 heme transporter
Overview
HRG1 has been identified as a cell surface and lysosomal heme transporter [398]. In addition, evidence suggests this 4TM‐containing protein associates with the V‐ATPase in lysosomes [367]. Recent studies confirm its lysosomal location and demonstrate that it has an important physiological function in macrophages ingesting senescent red blood cells (erythrophagocytosis), recycling heme (released from the red cell hemoglobin) from the phagolysosome into the cytosol, where the heme is subsequently catabolized to recycle the iron [511].
| Nomenclature | Heme transporter |
| Systematic nomenclature | SLC48A1 |
| Common abreviation | HRG1 |
| HGNC, UniProt | SLC48A1, Q6P1K1 |
Further Reading
Khan AA et al. (2013) Heme and FLVCR‐related transporter families SLC48 and SLC49. Mol. Aspects Med. 34: 669‐82 [PMID:23506900]
SLC49 family of FLVCR‐related heme transporters
Overview
FLVCR1 was initially identified as a cell‐surface attachment site for feline leukemia virus subgroup C [464], and later identified as a cell surface accumulation which exports heme from the cytosol [395]. A recent study indicates that an isoform of FLVCR1 is located in the mitochondria, the site of the final steps of heme synthesis, and appears to transport heme into the cytosol [89]. FLVCR‐mediated heme transport is essential for erythropoiesis. Flvcr1 gene mutations have been identified as the cause of PCARP (posterior column ataxia with retinitis pigmentosa (PCARP) [397].There are three paralogs of FLVCR1 in the human genome.
FLVCR2, most similar to FLVCR1 [319], has been reported to function as a heme importer [129]. In addition, a congenital syndrome of proliferative vasculopathy and hydranencephaly, also known as Fowler's syndrome, is associated with a loss‐of‐function mutation in FLVCR2 [340].
The functions of the other two members of the SLC49 family, MFSD7 and DIRC2, are unknown, although DIRC2 has been implicated in hereditary renal carcinomas [46].
| Nomenclature | Feline leukemia virus subgroup C cellular receptor family, member 1 | Feline leukemia virus subgroup C cellular receptor family, member 2 |
| Systematic nomenclature | SLC49A1 | SLC49A2 |
| Common abreviation | FLVCR1 | FLVCR2 |
| HGNC, UniProt | FLVCR1, Q9Y5Y0 | FLVCR2, Q9UPI3 |
| Substrates | heme [395] | heme [129] |
| Stoichiometry | Unknown | Unknown |
Comments
Non‐functional splice alternatives of FLVCR1 have been implicated as a cause of a congenital red cell aplasia, Diamond Blackfan anemia[405].
Further Reading
Khan AA et al. (2013) Heme and FLVCR‐related transporter families SLC48 and SLC49. Mol. Aspects Med. 34: 669‐82 [PMID:23506900]
Khan AA et al. (2011) Control of intracellular heme levels: heme transporters and heme oxygenases. Biochim. Biophys. Acta 1813: 668‐82 [PMID:21238504]
Krishnamurthy P et al. (2007) The role of transporters in cellular heme and porphyrin homeostasis. Pharmacol. Ther. 114: 345‐58 [PMID:17368550]
Latunde‐Dada GO et al. (2006) Recent advances in mammalian haem transport. Trends Biochem. Sci. 31: 182‐8 [PMID:16487711]
SLC50 sugar transporter
Overview
A mouse stromal cell cDNA library was used to clone C2.3 [463], later termed Rag1‐activating protein 1, with a sequence homology predictive of a 4TM topology. The plant orthologues, termed SWEETs, appear to be 7 TM proteins, with extracellular N‐termini, and the capacity for bidirectional flux of D‐glucose[82]. Expression of mouse SWEET in the mammary gland was suggestive of a role in Golgi lactose synthesis [82].
| Nomenclature | SLC50 sugar exporter |
| Systematic nomenclature | SLC50A1 |
| Common abreviation | RAG1AP1 |
| HGNC, UniProt | SLC50A1, Q9BRV3 |
Further Reading
Wright EM. (2013) Glucose transport families SLC5 and SLC50. Mol. Aspects Med. 34: 183‐96 [PMID:23506865]
Wright EM et al. (2011) Biology of human sodium glucose transporters. Physiol. Rev. 91: 733‐94 [PMID:21527736]
SLC51 family of steroid‐derived molecule transporters
Overview
The SLC51 organic solute transporter family of transporters is a pair of heterodimeric proteins which regulate bile salt movements in the bile duct, small intestine and kidney, and elsewhere, as part of the enterohepatic circulation [28, 109]. OSTα/OSTβ is also expressed in steroidogenic cells of the brain and adrenal gland, where it may contribute to steroid movement [154]. Bile acid transport is suggested to be facilitative and independent of sodium, potassium, chloride ions or protons [28, 109]. OSTα/OSTβ heterodimers have been shown to transport [3H]taurocholic acid, [3H]dehydroepiandrosterone sulphate, [3H]estrone‐3‐sulphate, [3H]pregnenolone sulphate and [3H]dehydroepiandrosterone sulphate [28, 109, 154]. OSTα is suggested to be a seven TM protein, while OSTβ is a single TM ‘ancillary’ protein, both of which are thought to have intracellular C‐termini [315]. Bimolecular fluorescence complementation studies suggest the possibility of OSTα homo‐oligomers, as well as OSTα/OSTβ hetero‐oligomers [92, 315].
| Nomenclature | Organic solute transporter subunit α | Organic solute transporter subunit β |
| Systematic nomenclature | SLC51A1 | SLC51A1BP |
| Common abreviation | OSTα | OSTβ |
| HGNC, UniProt | SLC51A, Q86UW1 | SLC51B, Q86UW2 |
Further Reading
Ballatori N. (2011) Pleiotropic functions of the organic solute transporter Ostα‐Ostβ. Dig Dis 29: 13‐7 [PMID:21691099]
Ballatori N et al. (2013) The heteromeric organic solute transporter, OSTα‐OSTβ/SLC51: a transporter for steroid‐derived molecules. Mol. Aspects Med. 34: 683‐92 [PMID:23506901]
Dawson PA. (2011) Role of the intestinal bile acid transporters in bile acid and drug disposition. Handb Exp Pharmacol 169‐203 [PMID:21103970]
SLC52 family of riboflavin transporters
Overview
riboflavin, also known as vitamin B2, is a precursor of the enzyme cofactors flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD). Riboflavin transporters are predicted to possess 10 or 11 TM segments.
| Nomenclature | solute carrier family 52 | solute carrier family 52 | solute carrier family 52 |
| (riboflavin transporter), member 1 | (riboflavin transporter), member 2 | (riboflavin transporter), member 3 | |
| Systematic nomenclature | SLC52A1 | SLC52A2 | SLC52A3 |
| Common abreviation | RFVT1 | RFVT2 | RFVT3 |
| HGNC, UniProt | SLC52A1, Q9NWF4 | SLC52A2, Q9HAB3 | SLC52A3, Q9NQ40 |
| Endogenous substrates | riboflavin (K m1.3 × 10−3M) [530] | riboflavin (K m9.8 × 10−4M) [530] | riboflavin (K m3.3 × 10−4M) [530] |
| Stoichiometry | Unknown | Unknown | H+‐dependent |
Comments
Although expressed elsewhere, RFVT3 is found on the luminal surface of intestinal epithelium and is thought to mediate uptake of dietary riboflavin, while RFVT1 and RFVT2 are thought to allow movement from the epithelium into the blood.
Further Reading
Yamamoto S et al. (2009) Identification and functional characterization of rat riboflavin transporter 2. J. Biochem. 145: 437‐43 [PMID:19122205]
Yonezawa A et al. (2013) Novel riboflavin transporter family RFVT/SLC52: identification, nomenclature, functional characterization and genetic diseases of RFVT/SLC52. Mol. Aspects Med. 34: 693‐701 [PMID:23506902]
Patched family
Overview
NPC1L1 acts in the gut epithelium to allow the accumulation of dietary cholesterol through a clathrin‐dependent mechanism. Ezetimibe is used to reduce cholesterol absorption through inhibition of NPC1L1.
| Nomenclature | NPC1‐like 1 |
| HGNC, UniProt | NPC1L1, Q9UHC9 |
| Selective antagonists | ezetimibe (Inhibition) (pK d 6.7) [21] |
SLCO family of organic anion transporting polypeptides
Overview
The SLCO superfamily is comprised of the organic anion transporting polypeptides (OATPs). The 11 human OATPs are divided into 6 families and ten subfamilies based on amino acid identity. These proteins are located on the plasma membrane of cells throughout the body. They have 12 TM domains and intracellular termini, with multiple putative glycosylation sites. OATPs mediate the sodium‐independent uptake of a wide range of amphiphilic substrates, including many drugs and toxins. Due to the multispecificity of these proteins, this guide lists classes of substrates and inhibitors for each family member. More comprehensive lists of substrates, inhibitors, and their relative affinities may be found in the review articles listed below.
| Nomenclature | OATP1A2 | OATP1B1 | OATP1B3 | OATP1C1 |
| Systematic nomenclature | SLCO1A2 | SLCO1B1 | SLCO1B3 | SLCO1C1 |
| HGNC, UniProt | SLCO1A2, P46721 | SLCO1B1, Q9Y6L6 | SLCO1B3, Q9NPD5 | SLCO1C1, Q9NYB5 |
| Substrates | fluoroquinolones, beta blockers, deltorphin II, rosuvastatin, fexofenadine, bromsulphthalein, anticancer drugs, antibiotics, HIV protease inhibitors, talinolol, ouabain, microcystin | statins, opioids, β‐lactam antibiotics, bile acid derivatives and conjugates, bromsulphthalein, anticancer drugs, HIV protease inhibitors, fexofenadine, antifungals, ACE inhibitors, rifampicin, endothelin receptor antagonists, sartans | rifampicin, opioids, sartans, statins, digoxin, anticancer drugs, bromsulphthalein, bile acid derivatives and conjugates, β‐lactam antibiotics, ouabain, amanitin, saquinavir, fexofenadine, erythromycin‐A, phalloidin | statins, bromsulphthalein |
| Endogenous substrates | bile acids, thyroid hormones, steroid conjugates, bilirubin, PGE2 | leukotrienes, steroid conjugates, thyroid hormones, bile acids, bilirubin | steroid conjugates, thyroid hormones, bile acids, CCK‐8 (CCK, P06307), bilirubin, LTC4 | thyroid hormones, steroid conjugates |
| Ligands | – | pravastatin (Binding) | – | – |
| Inhibitors | naringin [25], rifampicin, rifamycin SV | cyclosporin A, gemfibrozil [364], glycyrrhizin, indocyanine green, rifampicin, rifamycin SV, sildenafil | cyclosporin A (pIC50 6.1) [478], sildenafil (pIC50 6.1) [478], rifampicin (pIC50 5.8) [478], gemfibrozil, glycyrrhizin, rifamycin SV | DPDPE, probenecid, taurocholic acid |
| Labelled ligands | [3H]BSP, [3H]DPDPE, [3H]estrone‐3‐sulphate | [3H]estradiol‐17β‐glucuronide, [3H]estrone‐3‐sulphate | [3H]BSP, [3H]CCK‐8 (human, mouse, rat), [3H]estradiol‐17β‐glucuronide | [125I]thyroxine, [3H]BSP, [3H]estrone‐3‐sulphate |
| Comments | Although rat and mouse OATP1A4 are considered the orthologs of human OATP1A2 we do not cross‐link to gene or protein databases for these since in reality there are five genes in rodents that arose through gene duplication in this family and it is not clear which one of these is the "true" ortholog. | Other inhibitors include, fibrates, flavonoids, glitazones and macrolide antibiotics. pravastatin is used as a probe | Other inhibitors include, HIV protease inhibitors, glitazones and macrolide antibiotics | – |
| Nomenclature | OATP2A1 | OATP2B1 | OATP3A1 | OATP4A1 | OATP4C1 |
| Systematic nomenclature | SLCO2A1 | SLCO2B1 | SLCO3A1 | SLCO4A1 | SLCO4C1 |
| HGNC, UniProt | SLCO2A1, Q92959 | SLCO2B1, O94956 | SLCO3A1, Q9UIG8 | SLCO4A1, Q96BD0 | SLCO4C1, Q6ZQN7 |
| Substrates | synthetic prostaglandin derivatives | amiodarone, bromsulphthalein, statins, glibenclamide, aliskiren, fexofenadine, talinolol, bosentan, telmisartan | – | penicillin G | dipeptidyl peptidase‐4 inhibitors, anticancer drugs, cardiac glycosides |
| Endogenous substrates | prostaglandins, eicosanoids | estrone‐3‐sulphate, dehydroepiandrosterone sulphate, T4 | BQ123, vasopressin (AVP, P01185), thyroid hormones, prostaglandins | thyroid hormones, prostaglandins, bile acids, steroid conjugates | thyroid hormones, cyclic AMP, steroid conjugates |
| Inhibitors | bromocresol green (Inhibition of PGF2α uptake in PGT‐expressing HeLa cells) (pK i 5.4) [263] – Rat, bromsulphthalein (Inhibition of PGF2α uptake in PGT‐expressing HeLa cells) (pK i 5.2) [263] – Rat | gemfibrozil, glibenclamide, rifamycin SV | – | – | – |
| Labelled ligands | [3H]PGE2 (Binding) [78] | [3H]BSP, [3H]estrone‐3‐sulphate | [3H]PGE2, [3H]estrone‐3‐sulphate | [3H]estrone‐3‐sulphate | [3H]digoxin |
| Comments | Other inhibitors include NSAIDs | Other inhibitors include glitazones and citrus juices | – | – | – |
Further Reading
Gong IY et al. (2013) Impact of genetic variation in OATP transporters to drug disposition and response. Drug Metab. Pharmacokinet. 28: 4‐18 [PMID:23047721]
Hagenbuch B et al. (2013) The SLCO (former SLC21) superfamily of transporters. Mol. Aspects Med. 34: 396‐412 [PMID:23506880]
König J et al. (2013) Transporters and drug‐drug interactions: important determinants of drug disposition and effects. Pharmacol. Rev. 65: 944‐66 [PMID:23686349]
Obaidat A et al. (2012) The expression and function of organic anion transporting polypeptides in normal tissues and in cancer. Annu. Rev. Pharmacol. Toxicol. 52: 135‐51 [PMID:21854228]
Roth M et al. (2012) OATPs, OATs and OCTs: the organic anion and cation transporters of the SLCO and SLC22A gene superfamilies. Br. J. Pharmacol. 165: 1260‐87 [PMID:22013971]
Shitara Y et al. (2013) Clinical significance of organic anion transporting polypeptides (OATPs) in drug disposition: their roles in hepatic clearance and intestinal absorption. Biopharm Drug Dispos 34: 45‐78 [PMID:23115084]
Stieger B et al. (2014) Organic anion‐transporting polypeptides. Curr Top Membr 73: 205‐32 [PMID:24745984]
Alexander, S. PH. , Kelly, E. , Marrion, N. , Peters, J. A. , Benson, H. E. , Faccenda, E. , Pawson, A. J. , Sharman, J. L. , Southan, C. , Davies, J. A. , and CGTP Collaborators (2015) The Concise Guide to PHARMACOLOGY 2015/16: Transporters. British Journal of Pharmacology, 172: 6110–6202. doi: 10.1111/bph.13355.
References
- 1. Abbot EL et al (2006) [16331283]
- 2. Abramson J et al (2009) [19631523]
- 3. Aguirre P et al (2005) [15667655]
- 4. Agulhon C et al (2003) [12761825]
- 5. Albers A et al (2001) [11692272]
- 6. Almqvist J et al (2004) [15260472]
- 7. Amara SG et al (1993) [8103691]
- 8. Anderson CM et al (2008) [18599538]
- 9. Anderson CM et al (2009) [19074966]
- 10. Andrini O et al (2008) [18989094]
- 11. Aouameur R et al (2007) [17932225]
- 12. Apparsundaram S et al (2000) [11027560]
- 13. Apricò K et al (2004) [14994336]
- 14. Apricò K et al (2007) [17590480]
- 15., et al (2001) [11389172]
- 16. Arriza JL et al (1993) [8101838]
- 17. Arunotayanun W et al (2013) [23602445]
- 18. Ashikov A et al (2005) [15911612]
- 19. Assaraf YG et al (1998) [9525913]
- 20. Aubrey KR et al (2000) [10860934]
- 21. Auerbach SS et al National Toxicology Program: Dept of Health and Human Services. Accessed on 02/05/2014. DrugMatrix
- 22. Babu E et al (2003) [12930836]
- 23. Bagrov AY et al (2009) [19325075]
- 24. Bailey CG et al (2011) [21123949]
- 25. Bailey DG et al (2007) [17301733]
- 26. Bakos E et al (2007) [17187268]
- 27. Baldwin SA et al (2005) [15701636]
- 28. Ballatori N et al (2005) [16317684]
- 29. Banerjee A et al (2006) [16411770]
- 30. Bang‐Andersen B et al (2011) [21486038]
- 31. Barnes K et al (2006) [16873718]
- 32. Beart PM et al (2007) [17088867]
- 33. Bellocchio EE et al (2000) [10938000]
- 34. Ben‐Daniel R et al (2008) [18487050]
- 35. Bergeron R et al (1998) [9861038]
- 36. Betz H et al (2006) [16417482]
- 37. Bhardwaj RK et al (2006) [16289537]
- 38. Bhat BG et al (2003) [12810816]
- 39. Bianchi J et al (1986) [3945643]
- 40. Biegel A et al (2006) [16868651]
- 41. Bissonnette P et al (2004) [15181167]
- 42. Bizhanova A et al (2009) [19196800]
- 43. Blackburn C et al (2006) [16644217]
- 44. Blair BG et al (2009) [19509135]
- 45. Blasius AL et al (2010) [21045126]
- 46. Bodmer D et al (2002) [11912179]
- 47. Bodoy S et al (2005) [15659399]
- 48. Boll M et al (2002) [11959859]
- 49. Borden LA et al (1994) [7874447]
- 50. Borden LA et al (1994) [7851497]
- 51. Borst P et al (2007) [16586096]
- 52. Botka CW et al (2000) [11741232]
- 53. Boudker O et al (2007) [17230192]
- 54. Boulay D et al (2008) [18621075]
- 55. Bourgeois F et al (2005) [15613375]
- 56. Bravo DT et al (2005) [15979764]
- 57. Bravo D et al (2004) [15485505]
- 58. Brown A et al (2001) [11454468]
- 59. Bröer A et al (2002) [11850497]
- 60. Bröer A et al (2009) [19657969]
- 61. Bröer A et al (1999) [10537079]
- 62. Bröer A et al (2006) [16185194]
- 63. Bröer A et al (2000) [10698697]
- 64. Bröer S, (2006) [16540203]
- 65. Bröer S, (2008) [18400692]
- 66. Bröer S et al (2008) [19033659]
- 67. Burant CF et al (1992) [1634504]
- 68. Burger S et al (2011) [21742018]
- 69. Busch AE et al (1996) [8643577]
- 70. Böhmer C et al (2005) [15804236]
- 71. Carland JE et al (2013) [22978602]
- 72. Carlier PR et al (1998) [9871604]
- 73. Carroll FI et al (2009) [19821577]
- 74. Carroll FI et al (2004) [15566309]
- 75. Caulfield MJ et al (2008) [18842065]
- 76. Caulfield WL et al (2001) [11495577]
- 77. Cha SH et al (2000) [10660625]
- 78. Chan BS et al (1998) [9506966]
- 79. Chang MH et al (2009) [19365592]
- 80. Chao EC et al (2010) [20508640]
- 81. Cheeseman C, (2008) [18477702]
- 82. Chen LQ et al (2010) [21107422]
- 83. Chen NH et al (2004) [12719981]
- 84. Chen SY et al (2008) [18337460]
- 85. Chen Y et al (2007) [17495125]
- 86. Chen Z et al (2003) [12527723]
- 87. Chen Z et al (2003) [12727219]
- 88. Chen ZQ et al (2006) [16421098]
- 89. Chiabrando D et al (2012) [23187127]
- 90. Choi MK, (2012) [22644860]
- 91. Chong X et al (1992) [1417961]
- 92. Christian WV et al (2012) [22535958]
- 93. Clausen RP et al (2006) [17175818]
- 94. Coady MJ et al (2007) [17526579]
- 95. Coady MJ et al (2002) [12133831]
- 96. Cohen‐Kfir E et al (2005) [15829583]
- 97. Colleoni S et al (2008) [18451317]
- 98. Colton CK et al (2010) [20508255]
- 99. Coon et al (2004) Abstract Viewer/Itinerary Planner, Program No. 168.10. Society for Neuroscience:.
- 100. Counillon L et al (1993) [8246907]
- 101. Craddock AL et al (1998) [9458785]
- 102. Cuboni S et al (2014) [25318072]
- 103. Dai W et al (1999) [9882430]
- 104. Dalton TP et al (2005) [15722412]
- 105. Daniel H et al (2004) [12905028]
- 106. Daniels G et al (2015) [25896650]
- 107. Darcel NP et al (2005) [15930458] [DOI] [PubMed]
- 108. Dawson LA et al (2009) [19499624]
- 109. Dawson PA et al (2005) [15563450]
- 110. Dawson PA et al (2009) [19498215]
- 111. De Domenico I et al (2007) [17077321]
- 112. De Domenico I et al (2005) [15956209]
- 113. DeStefano GM et al (2014) [24831815]
- 114. Delpire E et al (2009) [19279215]
- 115. Dennis M et al (2013) Compositions and methods for the diagnosis and treatment of tumor. Patent number: US8535675 B2. Assignee: Genentech, Inc.. Priority date: 30/11/2009. Publication date: 17/09/2013.
- 116. Dhar TG et al (1994) [8057281]
- 117. Dhar TGM et al (1996) Bioorg Med Chem Letts 6: 1535–1540 [Google Scholar]
- 118. Di Daniel E et al (2009) [19607714]
- 119. Diaz GA et al (1999) [10391223]
- 120. Diez‐Sampedro A et al (2003) [13130073]
- 121. Dodd JR et al (2007) [17400549]
- 122. Doege H et al (2001) [11583593]
- 123. Dohán O et al (2007) [18077370]
- 124. Dong H et al (2002) [11916852]
- 125. Dong Z et al (2013) [23339484]
- 126. Donovan A et al (2005) [16054062]
- 127. Dorwart MR et al (2007) [17673510]
- 128. Dreyfus N et al (2013) [24900709]
- 129. Duffy SP et al (2010) [20823265]
- 130. Dunlop J, (2006) [16368269]
- 131. Dunlop J et al (2006) [17017964]
- 132. Dunlop J et al (2003) [14517179]
- 133. Dunlop J et al (2005) [16014807]
- 134. Dutta B et al (1999) [10542220]
- 135. Döring F et al (1998) [9637710]
- 136. Edington AR et al (2009) [19875446]
- 137. Edwards N et al (2011) [20691150]
- 138. Efange SM et al (1995) [7702637]
- 139. Eiden LE et al (2004) [12827358]
- 140. Eiden LE et al (2011) [21272013]
- 141. Eliasof S et al (2001) [11299317]
- 142. Elliott AM et al (2009) [19147539]
- 143. Endeward V et al (2008) [17712059]
- 144. Engel K et al (2005) [16099839]
- 145. Enomoto A et al (2002) [12024214]
- 146. Erickson JD et al (1993) [8245983]
- 147. Erickson JD et al (1996) [8643547]
- 148. Erickson JD et al (1994) [8071310]
- 149. Eskandari S et al (1997) [9341168]
- 150. Esslinger CS et al (2005) [16183084]
- 151. Esslinger CS et al (2005) [15670919]
- 152. Eulenburg V et al (2005) [15950877]
- 153. Faergeman NJ et al (1997) [9079682]
- 154. Fang F et al (2010) [20649839]
- 155. Fattorini G et al (2009) [19627441]
- 156. Favari E et al (2004) [15514211]
- 157. Fei YJ et al (2000) [10823827]
- 158. Ferguson SM et al (2004) [15173594]
- 159. Ferguson SM et al (2004) [14993474]
- 160. Fernandes CF et al (2007) [17632081]
- 161. Fiermonte G et al (2003) [12807890]
- 162. Fiermonte G et al (2009) [19429682]
- 163. Fish PV et al (2008) [18387300]
- 164. Foltz M et al (2005) [15504109]
- 165. Fontana AC et al (2003) [12890709]
- 166. Fontana AC et al (2007) [17646426]
- 167. Forrest LR et al (2009) [19996368]
- 168. Forster IC et al (1999) [10198426]
- 169. Friesema EC et al (2006) [16887882]
- 170. Froimowitz M et al (2007) [17228864]
- 171. Fu Y et al (2013) [23931754]
- 172. Fujimori Y et al (2008) [18583547]
- 173. Fujinami K et al (2015) [25312043]
- 174. Fülep GH et al (2006) [16766089]
- 175. Gabernet L et al (2005) [15555781]
- 176. Gameiro A et al (2011) [21641307]
- 177. Ganapathy ME et al (1995) [7592745]
- 178. Ganapathy ME et al (1998) [9610386]
- 179. Ganapathy V et al (2008) [18446519]
- 180. Ganapathy V et al (2009) [18992769]
- 181. Ganel R et al (2006) [16274998]
- 182. Gasnier B, (2004) [12750892]
- 183. Gasnier B, (2000) [10865121]
- 184. Gebhardt FM et al (2010) [20688910]
- 185. Gendreau S et al (2004) [15265858]
- 186. Gengo PJ et al (2005) J Urol 173: Abstract 878 [Google Scholar]
- 187. Geyer J et al (2007) [17491011]
- 188. Geyer J et al (2008) [18355966]
- 189. Geyer J et al (2004) [15020217]
- 190. Gimeno RE et al (2003) [12556534]
- 191. Girijashanker K et al (2008) [18270315]
- 192. Glennon RA et al (2000) [10715164]
- 193. Godoy JR et al (2007) [17628207]
- 194. Gomeza J et al (2006) [16722246]
- 195. Gomeza J et al (2003) [14622582]
- 196. Gomeza J et al (2003) [14622583]
- 197. Gopal E et al (2005) [15651982]
- 198. Gorboulev V et al (1997) [9260930]
- 199. Goursaud S et al (2011) [21730107]
- 200. Goytain A et al (2005) [15809054]
- 201. Goytain A et al (2005) [15713785]
- 202. Graf J et al (2005) [15714523]
- 203. Greinacher A et al (2010) [20037594]
- 204. Grempler R et al (2012) [21985634]
- 205. Grewer C et al (2005) [16128593]
- 206. Grewer C et al (2004) [15107471]
- 207. Grewer C et al (2005) [15834685]
- 208. Grunewald M et al (2000) [10734120]
- 209. Gründemann D et al (1999) [10385678]
- 210. Gu H et al (1994) [8125921]
- 211. Gu HH et al (1996) [8636118]
- 212. Gunshin H et al (1997) [9242408]
- 213. Gupta N et al (2006) [16375929]
- 214. Hager K et al (1995) [7537337]
- 215. Hallén S et al (1999) [10471288]
- 216. Hammond JR, (2000) [10763851]
- 217. Hammond JR et al (2004) [14634039]
- 218. Han H et al (1998) [9706043]
- 219. Han X et al (2006) [16734743]
- 220. Hannaert P et al (2002) [11882915]
- 221. Harvey RJ et al (2008) [18707791]
- 222. Hatanaka T et al (2001) [11342143]
- 223. Hatanaka T et al (2000) [10930503]
- 224. Hatanaka T et al (2001) [11306607]
- 225. Heffernan GD et al (2009) [19836247]
- 226. Heinrich T et al (2004) [15341484]
- 227. Helias V et al (2012) [22246506]
- 228. Hemker MB et al (2003) [12846905]
- 229. Herdon HJ et al (2010) [20691713]
- 230. Herrera‐Ruiz D et al (2003) [12661057]
- 231. Ho HT et al (2011) [21816955]
- 232. Hollingworth P et al (2011) [21460840]
- 233. Hsu CL et al (2012) [22174130]
- 234. Hu Z et al (2000) [10615129]
- 235. Huang S et al (2009) [19074430]
- 236. Hummel CS et al (2011) [20980548]
- 237. Hägglund MG et al (2011) [21511949]
- 238. Ibberson M et al (2000) [10671487]
- 239. Ichida K et al (2003) [12472777]
- 240. Iharada M et al (2010) [20566650]
- 241. Inagaki N et al (1995) [7502040]
- 242. Inazu M et al (2005) [16000150]
- 243. Ishida N et al (1998) [9644260]
- 244. Ishida N et al (2005) [15607426]
- 245. Ishida N et al (1996) [9010752]
- 246. Ishida N et al (1999) [10393322]
- 247. Ishida S et al (2002) [12370430]
- 248. Itagaki S et al (2006) [16729224]
- 249. Ito S et al (2010) [20065018]
- 250. Ito Y et al (2001) [11527541]
- 251. Iwamoto H et al (2006) [17005849]
- 252. Jensen AA et al (2009) [19161278]
- 253. Jeong HJ et al (2010) [20860669]
- 254. Jiang J et al (2011) [20708631]
- 255. Jonas MC et al (2010) [20826464]
- 256. Jost N et al (2013) [23647096]
- 257. Ju P et al (2004) [15031290]
- 258. Juge N et al (2010) [20920794]
- 259. Juge N et al (2009) [19843525]
- 260. Kamakura A et al (2008) [18952056]
- 261. Kamiyama S et al (2006) [16492677]
- 262. Kamiyama S et al (2003) [12716889]
- 263. Kanai N et al (1995) [7754369]
- 264. Kanai Y et al (2004) [14530974]
- 265. Kanai Y et al (2003) [14612154]
- 266. Kanai Y et al (1994) [8282810]
- 267. Kanamori A et al (1997) [9096318]
- 268. Kang N et al (2010) [20595384]
- 269. Kang SY et al (2010) [20637636]
- 270. Karunakaran S et al (2008) [18522536]
- 271. Kashiwayama Y et al (2009) [19010322]
- 272. Katsuno K et al (2007) [17050778]
- 273. Kemp S et al (2011) [21488864]
- 274. Kennedy DJ et al (2005) [15644866]
- 275. Kerr ID et al (2011) [21175590]
- 276. Khare P et al (2010) [20225888]
- 277. Kim K et al (2011) [21792905]
- 278. Kim KH et al (2005) [15591059]
- 279. Kim RB et al (1999) [10565843]
- 280. Kimura H et al (2002) [11907186]
- 281. Klaassen CD et al (2010) [20103563]
- 282. Knutsen LJ et al (1999) [10479278]
- 283. Knütter I et al (2001) [11284702]
- 284. Koch HP et al (2007) [17360917]
- 285. Koch HP et al (1999) [10570036]
- 286. Koldamova R et al (2014) [24844148]
- 287. Kolisek M et al (2012) [22031603]
- 288. Kommareddi PK et al (2010) [20665236]
- 289. Kouji H et al (2009) [19135976]
- 290. Krishnamurthy PC et al (2006) [17006453]
- 291. Krishnaswamy A et al (2009) [19186169]
- 292. Kristensen AS et al (2011) [21752877]
- 293. Kung MP et al (1994) [7855735]
- 294. Kusuhara H et al (1999) [10224140]
- 295. Kvist T et al (2009) [19275529]
- 296. Lapinsky DJ et al (2009) [19442525]
- 297. Lapinsky DJ et al (2011) [21129986]
- 298. Larráyoz IM et al (2006) [16837649]
- 299. Larsen M et al (2009) [19594759]
- 300. Larsen MH et al (2008) [17950272]
- 301. Lau CL et al (2011) [21309758]
- 302. Leary GP et al (2007) [17360916]
- 303. Lee A et al (2010) [20883814]
- 304. Lee J et al (2002) [11734551]
- 305. Lee J et al (2009) [19570976]
- 306. Lee SG et al (2008) [18326497]
- 307. Lee SH et al (2008) [18269914]
- 308. Lee YC et al (2010) [20639396]
- 309. Leier I et al (1994) [7961706]
- 310. Leung DDM et al (2010) Anti‐ferroportin 1 monoclonal antibodies and uses thereof. Patent number: WO2010065496 A1. Assignee: Eli Lilly And Company.. Priority date: 05/12/2008. Publication date: 10/06/2010.
- 311. Levy LM et al (1998) [9822723]
- 312. Lewis SE et al (2001) [11470793]
- 313. Li AR et al (2011) [21398124]
- 314. Li H et al (2008) [17928635]
- 315. Li N et al (2007) [17650074]
- 316. Liang Y et al (2012) [22355316]
- 317. Lin P et al (2008) [19061983]
- 318. Lin X et al (2009) [19032932]
- 319. Lipovich L et al (2002) [11943475]
- 320. Liu H et al (2008) [18983139]
- 321. Liu Z et al (2008) [18037372]
- 322. Liuzzi JP et al (2006) [16950869]
- 323. Lowe JA 3rd et al (2003) [12657266]
- 324. Lytton J et al (1991) [1832668]
- 325. Lühn K et al (2001) [11326279]
- 326. MacDonald L et al (2002) [11895172]
- 327. Machtens JP et al (2011) [21572047]
- 328. Maciver B et al (2008) [18256317]
- 329. Madsen KK et al (2010) [20026354]
- 330. Mak DO et al (2006) [16131648]
- 331. Mallorga PJ et al (2003) [12941372]
- 332. Manolescu AR et al (2007) [17710649]
- 333. Martens H et al (2008) [19052203]
- 334. Masuda S et al (2006) [16807400]
- 335. McIntire SL et al (1997) [9349821]
- 336. Meier PJ et al (1997) [9398014]
- 337. Merlin D et al (1998) [9835627]
- 338. Metzner L et al (2004) [14718599]
- 339. Metzner L et al (2005) [16126914]
- 340. Meyer E et al (2010) [20206334]
- 341. Mezler M et al (2008) [18815213]
- 342. Michel V et al (2009) [19357133]
- 343. Michel V et al (2006) [16636297]
- 344. Mihalik SJ et al (2002) [11980911]
- 345. Miki T et al (1999) [10194514]
- 346. Milger K et al (2006) [17062637]
- 347. Mistrík P et al (2012) [22890707]
- 348. Miura N et al (1996) [8889805]
- 349. Miyaji T et al (2011) [21781115]
- 350. Miyauchi S et al (2004) [14966140]
- 351. Miyazaki E et al (2001) [11641397]
- 352., et al (2012) [22420844]
- 353. Murakami Y et al (2005) [16174808]
- 354. Muraoka M et al (2001) [11322953]
- 355. Nair TS et al (2004) [14973250]
- 356. Nakai Y et al (2007) [17475902]
- 357. Nakamura N et al (2005) [15522866]
- 358. Nakamura T et al (2010) [20410607]
- 359. Nakanishi T et al (2001) [11243884]
- 360. Newstead S et al (2011) [21131908]
- 361. Newton JM et al (2001) [11574907]
- 362. Nothmann D et al (2011) [21127051]
- 363. Noyer M et al (1995) [8605950]
- 364. Noé J et al (2007) [17470528]
- 365. Numata M et al (2001) [11279194]
- 366. Núnez E et al (2000) [10694221]
- 367. O'Callaghan KM et al (2010) [19875448]
- 368. O'Neill DJ et al (2010) [20462211]
- 369. Ohta KY et al (2006) [16928787]
- 370. Okuda T et al (2003) [12675135]
- 371. Okuda T et al (2000) [11068039]
- 372. Oppedisano F et al (2010) [20599776]
- 373. Ordovás L et al (2006) [17065791]
- 374. Otsuka M et al (2005) [16330770]
- 375. Oude Elferink RP et al (2007) [16622704]
- 376. Owen RP et al (2006) [16840788]
- 377. Owens MJ et al (1997) [9400006]
- 378. Palacín M et al (1998) [9790568]
- 379. Pan CJ et al (2011) [21949678]
- 380. Paytubi S et al (2009) [19570978]
- 381. Pearlman RJ et al (2003) [12558979]
- 382. Pechulis AD et al (2012) [23084899]
- 383. Pestov NB et al (2006) [16525125]
- 384. Pillai SM et al (2011) [21097500]
- 385. Pinard E et al (2010) [20491477]
- 386. Pinilla‐Tenas J et al (2003) [14502423] [DOI] [PubMed]
- 387. Pochini L et al (2014) [24704252]
- 388. Pondarre C et al (2007) [17192398]
- 389. Prasad PD et al (1995) [7826387]
- 390. Prasad PD et al (2000) [10772912]
- 391. Pristupa ZB et al (1994) [8302271]
- 392. Pérez‐Siles G et al (2011) [21574997]
- 393. Qiu A et al (2006) [17129779]
- 394. Quazi F et al (2014) [24707049]
- 395. Quigley JG et al (2004) [15369674]
- 396. Raffel DM et al (2004) [15300361]
- 397. Rajadhyaksha AM et al (2010) [21070897]
- 398. Rajagopal A et al (2008) [18418376]
- 399. Rajgopal A et al (2001) [11731220]
- 400. Ravera S et al (2007) [17494632]
- 401. Rees EM et al (2004) [15494390]
- 402. Rehmann H, (2012) [22260657]
- 403. Reid G et al (2003) [12835412]
- 404. Reith ME et al (1996) [8878059]
- 405. Rey MA et al (2008) [18815190]
- 406. Reyes N et al (2009) [19924125]
- 407. Rice AE et al (2009) [19150361]
- 408. Ripoche P et al (2004) [15572441]
- 409. Rogers S et al (2003) [12914765]
- 410. Romano A et al (2010) [19913073]
- 411. Romera C et al (2007) [17213861]
- 412. Rose EM et al (2009) [19553454]
- 413. Rotella DP et al (2009) [19720528]
- 414. Rothstein JD et al (2005) [15635412]
- 415. Rousseau F et al (2008) [18815261]
- 416. Rubio‐Aliaga I et al (2008) [18668438]
- 417. Ryan RM et al (2007) [17435767]
- 418. Ryan RM et al (2004) [14982939]
- 419. Sabatucci JP et al (2010) [20378347]
- 420. Sagné C et al (2001) [11390972]
- 421. Sahni J et al (2013) [23506895]
- 422. Said HM. (2009) [19056639]
- 423. Said HM et al (1989) [2911998]
- 424. Saier MH et al (2009) [19022853]
- 425. Saito K et al (2010) [21190592]
- 426. Sakata K et al (2001) [11336635]
- 427. Salazar G et al (2009) [19521526]
- 428. Salojin KV et al (2011) [21346251]
- 429. Sandoval A et al (2010) [19913517]
- 430. Sasawatari S et al (2011) [21277849]
- 431. Sawada K et al (2008) [18375752]
- 432. Schaffer JE et al (1994) [7954810]
- 433. Schatton T et al (2008) [18202660]
- 434. Schirmer SU et al (2011) [21482687]
- 435. Schiöth HB et al (2013) [23506890]
- 436. Schlipf NA et al (2010) [20461110]
- 437. Schousboe A et al (2011) [21428813]
- 438. Schousboe A et al (2004) [15451399]
- 439. Secondo A et al (2015) [25942323]
- 440. Seidler NW et al (1989) [2530215]
- 441. Sekler I. (2015) [25998733]
- 442. Semyanov A et al (2004) [15111008]
- 443. Shigeri Y et al (2001) [11677257]
- 444. Shimamoto K et al (1998) [9463476]
- 445. Shimamoto K et al (2007) [17047096]
- 446. Shimamoto K et al (2000) [11078189]
- 447. Shimokawa N et al (2002) [12417639]
- 448. Shintre CA et al (2013) [23716676]
- 449. Sievert MK et al (1997) [9325342]
- 450. Singer D et al (2009) [19478081]
- 451. Singh N et al (2010) [20601425]
- 452. Singh SK et al (2007) [17687333]
- 453. Sloan JL et al (1999) [10446133]
- 454. Stahl A et al (1999) [10518211]
- 455. Stewart G. (2011) [21449978]
- 456. Stieger B. (2009) [19684528]
- 457. Sun Y et al (2009) [19115956]
- 458. Sundaram M et al (1998) [9705281]
- 459. Supplisson S et al (2002) [12354619]
- 460. Suzuki H et al (1998) [9875554]
- 461. Suzuki T et al (2005) [15994300]
- 462. Sweetnam PM et al (1993) [8496700]
- 463. Tagoh H et al (1996) [8630032]
- 464. Tailor CS et al (1999) [10400745]
- 465. Talvenheimo J et al (1983) [6853478]
- 466. Tamarappoo BK et al (1996) [8603078]
- 467. Tanihara Y et al (2007) [17509534]
- 468. Tatsumi M et al (1997) [9537821]
- 469. Terada T et al (2006) [16850272]
- 470. Thangaraju M et al (2006) [16873376]
- 471. Thangaraju M et al (2006) [17178845]
- 472. Theis S et al (2002) [11752223]
- 473. Thomsen C et al (1997) [9134205]
- 474. Thwaites DT et al (2011) [21501141]
- 475. Tollefson MB et al (2003) [14552767]
- 476. Torres‐Salazar D et al (2007) [17908688]
- 477. Traiffort E et al (2005) [15715662]
- 478. Treiber A et al (2007) [17496208]
- 479. Tsai G et al (2004) [15159536]
- 480. Tse CM et al (1993) [8415663]
- 481. Tse CM et al (1993) [7685025]
- 482. Tsuda M et al (2009) [19164462]
- 483. Tsukaguchi H et al (1999) [10331392]
- 484. Tzschentke TM et al (2007) [17656655]
- 485. Tóth A et al (2002) [12054538]
- 486. Uchida Y et al (2009) [19122366]
- 487. Uldry M et al (2002) [12135767]
- 488. Umapathy NS et al (2004) [15290873]
- 489. Utsunomiya‐Tate N et al (1996) [8662767]
- 490. Van Orden LJ et al (2013) [23347683]
- 491. Vandenberg RJ et al (2004) [15324920]
- 492. Vandenberg RJ et al (1997) [9145919]
- 493. Vandenberg RJ et al (2007) [17383967]
- 494. Vanslambrouck JM et al (2010) [20377526]
- 495. Varoqui H et al (1996) [8910293]
- 496. Vavricka SR et al (2004) [15521010]
- 497. Verheijen FW et al (1999) [10581036]
- 498. Veruki ML et al (2006) [17041592]
- 499. Vickers T et al (2008) [18468895]
- 500. Visser WE et al (2010) [19682536]
- 501. Voss AA et al (2007) [17110502]
- 502. Wallgard E et al (2008) [18483404]
- 503. Wang C et al (2013) [24021350]
- 504. Wang D et al (2003) [14634667]
- 505. Wang H et al (1999) [10329687]
- 506. Wang Q et al (2006) [16707723]
- 507. Warraich S et al (2013) [23184610]
- 508. Watanabe K et al (2002) [12132663]
- 509. Weinman SA et al (1998) [9856990]
- 510. Westhoff CM et al (2002) [11861637]
- 511. White C et al (2013) [23395172]
- 512. White HS et al (2005) [15550575]
- 513. Wiles AL et al (2006) [16899062]
- 514. Wille S et al (2001) [11698453]
- 515. Wojcik SM et al (2006) [16701208]
- 516. Wolf S et al (2002) [12049641]
- 517. Wong EH et al (2000) [10812041]
- 518. Wright EM et al (2011) [21527736]
- 519. Wright EM et al (2004) [12748858]
- 520. Wu CA et al (2004) [15140889]
- 521. Wu X et al (2002) [12504846]
- 522. Wu Y et al (2013) [23678871]
- 523. Wängler B et al (2004) [15380228]
- 524. Yabuki M et al (2009) [19236841]
- 525. Yamada T et al (2011) [21185344]
- 526. Yamamoto S et al (2010) [20042597]
- 527. Yamashita A et al(2005, ed.)[16041361]
- 528. Yamashita T et al (1997) [9092568]
- 529. Yao SY et al (2011) [21795683]
- 530. Yao Y et al (2010) [20463145]
- 531. Yasujima T et al (2010) [20047987]
- 532. Yee BK et al (2006) [16554468]
- 533. Yernool D et al (2004) [15483603]
- 534. Youngblood GL et al (2004) [15068970]
- 535. Yu XC et al (2009) [19159658]
- 536. Yu Z et al (2007) [17325024]
- 537. Zaia KA et al (2009) [19147495]
- 538. Zambrowicz B et al (2012) [22739142]
- 539. Zander JF et al (2010) [20519538]
- 540. Zeng Z et al (2008) [18355687]
- 541. Zerangue N et al (1996) [8910405]
- 542. Zerangue N et al (1996) [8857541]
- 543. Zerangue N et al (1996) [8782106]
- 544. Zhang HX et al (2009) [19433577]
- 545. Zhang X et al (2009) [19515813]
- 546. Zhao D et al (2007) [17506977]
- 547. Zhao R et al (2002) [11997266]
- 548. Zhou LM et al (1997) [8996224]
- 549. Zhou W et al (2010) [20448275]
- 550. Zhu HJ et al (2010) [20402963]
- 551. Zhu L et al (2009) [19632829]
- 552. Zidi‐Yahiaoui N et al (2009) [19553567]
- 553. Zipp GG et al (2014) [25037917]
- 554. Zou S et al (2011) [21426345]
- 555. Zuo Y et al (2008) [18957418]
- 556. de Carvalho FD et al (2011) [20980265]
- 557. van Leeuwen EM et al (2015) [25751400]
- 558. van Roermund CW et al (2011) [21145416]