Abstract
The Concise Guide to PHARMACOLOGY 2019/20 is the fourth in this series of biennial publications. The Concise Guide provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (http://www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide represents approximately 400 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point‐in‐time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.14753. Transporters are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein‐coupled receptors, ion channels, nuclear hormone receptors, catalytic receptors and enzymes. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid‐2019, and supersedes data presented in the 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC‐IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.
1.
Conflict of interest
The authors state that there are no conflicts of interest to disclose.
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 membrane proteins in the human genome, after the G protein‐coupled receptors, are the SLC solute carrier family. Within the solute carrier family, there are 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 65 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 orphan transporters, in as much as a physiological function has yet to be dtermined. Within the SLC super‐family, 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 co‐transport 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
S399 ATP‐binding cassette transporter family
S404 ABCD subfamily of peroxisomal ABC transporters
S406 F‐type and V‐type ATPases
S409 Phospholipid‐transporting ATPases
S409 SLC superfamily of solute carriers
S410 SLC1 family of amino acid transporters
S410 Glutamate transporter subfamily
S412 Alanine/serine/cysteine transporter subfamily
S413 SLC2 family of hexose and sugar alcohol transporters
S415 Proton‐coupled inositol transporter
S415 SLC3 and SLC7 families of heteromeric amino acid transporters (HATs)
S417 SLC4 family of bicarbonate transporters
S418 Sodium‐dependent HCO3 ‐ transporters
S418 SLC5 family of sodium‐dependent glucose transporters
S419 Hexose transporter family
S422 Sodium myo‐inositol cotransporter transporters
S423 SLC6 neurotransmitter transporter family
S423 Monoamine transporter subfamily
S424 GABA transporter subfamily
S425 Glycine transporter subfamily
S427 Neutral amino acid transporter subfamily
S428 SLC8 family of sodium/calcium exchangers
S429 SLC9 family of sodium/hydrogen exchangers
S429 SLC10 family of sodium‐bile acid co‐transporters
S431 SLC11 family of proton‐coupled metal ion transporters
S431 SLC12 family of cation‐coupled chloride transporters
S433 SLC13 family of sodium‐dependent sulphate/carboxylate transporters
S434 SLC14 family of facilitative urea transporters
S435 SLC15 family of peptide transporters
S437 SLC16 family of monocarboxylate transporters
S438 SLC17 phosphate and organic anion transporter family
S438 Type I sodium‐phosphate co‐transporters
S439 Vesicular glutamate transporters (VGLUTs)
S440 Vesicular nucleotide transporter
S440 SLC18 family of vesicular amine transporters
S442 SLC19 family of vitamin transporters
S443 SLC20 family of sodium‐dependent phosphate transporters
S443 SLC22 family of organic cation and anion transporters
S444 Organic cation transporters (OCT)
S445 Organic zwitterions/cation transporters (OCTN)
S446 Organic anion transporters (OATs)
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=200
S447 Atypical SLC22B subfamily
S448 SLC23 family of ascorbic acid transporters
S449 SLC24 family of sodium/potassium/calcium exchangers
S450 SLC25 family of mitochondrial transporters
S450 Mitochondrial di‐ and tri‐carboxylic acid transporter subfamily
S451 Mitochondrial amino acid transporter subfamily
S452 Mitochondrial phosphate transporters
S452 Mitochondrial nucleotide transporter subfamily
S453 Mitochondrial uncoupling proteins
S454 Miscellaneous SLC25 mitochondrial transporters
S454 SLC26 family of anion exchangers
S454 Selective sulphate transporters
S455 Chloride/bicarbonate exchangers
S456 Other SLC26 anion exchangers
S457 SLC27 family of fatty acid transporters
S458 SLC28 and SLC29 families of nucleoside transporters
S461 SLC30 zinc transporter family
S461 SLC31 family of copper transporters
S462 SLC32 vesicular inhibitory amino acid transporter
S463 SLC33 acetylCoA transporter
S464 SLC34 family of sodium phosphate co‐transporters
S465 SLC35 family of nucleotide sugar transporters
S466 SLC36 family of proton‐coupled amino acid transporters
S468 SLC37 family of phosphosugar/phosphate exchangers
S468 SLC38 family of sodium‐dependent neutral amino acid transporters
S469 System A‐like transporters
S469 System N‐like transporters
S470 Orphan SLC38 transporters
S470 SLC39 family of metal ion transporters
S472 SLC41 family of divalent cation transporters
S473 SLC42 family of Rhesus glycoprotein ammonium transporters
S473 SLC43 family of large neutral amino acid transporters
S474 SLC44 choline transporter‐like family
S475 SLC45 family of putative sugar transporters
S475 SLC46 family of folate transporters
S477 SLC47 family of multidrug and toxin extrusion transporters
S478 SLC49 family of FLVCR‐related heme transporters
S479 SLC51 family of steroid‐derived molecule transporters
S480 SLC52 family of riboflavin transporters
S481 SLC54 Mitochondrial pyruvate carriers
S482 SLC55 Mitochondrial cation/proton exchangers
S483 SLC57 NiPA‐like magnesium transporter family
S483 SLC58 MagT‐like magnesium transporter family
S484 SLC59 Sodium‐dependent lysophosphatidylcholine symporter family
S484 SLC60 Glucose transporters
S485 SLC61 Molybdate transporter family
S485 SLC62 Pyrophosphate transporters
S486 SLC63 Sphingosine‐phosphate transporters
S486 SLC64 Golgi Ca2+/H+ exchangers
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=136
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.
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=151
Overview
To date, 12 members of the human ABCA subfamily are identified. They share a high degree of sequence conservation and have been mostly related with lipid trafficking in a wide range of body locations. Mutations in some of these genes have been described to cause severe hereditary diseases related with lipid transport, such as fatal surfactant deficiency or harlequin ichthyosis. In addition, most of them are hypothesized to participate in the subcellular sequestration of drugs, thereby being responsible for the resistance of several carcinoma cell lines against drug treatment [http://www.ncbi.nlm.nih.gov/pubmed/16586097?dopt=AbstractPlus].
Comments
A number of structural analogues are not found in man: Abca14 (http://www.ensembl.org/Mus_musculus/Gene/Summary?g=ENSMUSG00000062017;r=7:127347475‐127468866); Abca15 (http://www.ensembl.org/Mus_musculus/Gene/Summary?g=ENSMUSG00000054746;r=7:127472198‐127551201); Abca16 (http://www.ensembl.org/Mus_musculus/Gene/Summary?g=ENSMUSG00000051900;r=7:127553161‐127688327) and Abca17 (http://www.ensembl.org/Mus_musculus/Gene/Summary?g=ENSMUSG00000035435;r=17:24401204‐24487974).
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=152
Overview
The ABCB subfamily is composed of four full transporters and two half transporters. This is the only human subfamily to have both half and full types of transporters. ABCB1 was discovered as a protein overexpressed in certain drug resistant tumor cells. It is expressed primarily in the blood brain barrier and liver and is thought to be involved in protecting cells from toxins. Cells that overexpress this protein exhibit multi‐drug resistance [http://www.ncbi.nlm.nih.gov/pubmed/11441126?dopt=AbstractPlus].
| Nomenclature | http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=768 | http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=769 | http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=770 |
| Common abbreviation | MDR1, PGP1 | TAP1 | TAP2 |
| HGNC, UniProt | https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:40, http://www.uniprot.org/uniprot/P08183 | https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:43, http://www.uniprot.org/uniprot/Q03518 | https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:44, http://www.uniprot.org/uniprot/Q03519 |
| 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 is a hetero‐dimer composed of the two half‐transporters, TAP1 (ABCB2) and TAP2 (ABCB3). The transporter shuttles peptides into the endoplasmic reticulum where they are loaded onto major histocompatibility complex class I (MHCI) molecules via the macromoldecular peptide‐loading complex and are eventually presented at the cell surface, attributing to TAP an important role in the adaptive immune response [http://www.ncbi.nlm.nih.gov/pubmed/24923865?dopt=AbstractPlus]. | |
| Nomenclature | http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=777 | http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=778 |
| Common abbreviation | MTABC2 | ABC16 |
| HGNC, UniProt | https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:41, http://www.uniprot.org/uniprot/Q9NRK6 | https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:42, http://www.uniprot.org/uniprot/O95342 |
| Ligands | – | http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4545 (Binding) (pK i 5.2) [http://www.ncbi.nlm.nih.gov/pubmed/12404239?dopt=AbstractPlus] |
| Comments | Mitochondrial location; the first human ABC transporter to have a crystal structure reported [http://www.ncbi.nlm.nih.gov/pubmed/23716676?dopt=AbstractPlus]. ABCB10 is important in early steps of heme synthesis in the heart and is required for normal red blood cell development [http://www.ncbi.nlm.nih.gov/pubmed/23720443?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/22085049?dopt=AbstractPlus]. | Loss‐of‐function mutations are associated with progressive familial intrahepatic cholestasis type 2 [http://www.ncbi.nlm.nih.gov/pubmed/19684528?dopt=AbstractPlus]. ATP‐dependent transport of bile acids into the confines of the canalicular space by ABCB11 (BSEP) generates an osmotic gradient and thereby, bile flow. Mutations in BSEP that decrease its function or expression cause Progressive Familial Cholestasis Type 2 (PFIC2), which in severe cases, can be fatal in the absence of a liver transplant. Drugs that inhibit BSEP function with IC50 values less than 25 μM [http://www.ncbi.nlm.nih.gov/pubmed/20829430?dopt=AbstractPlus] or decrease its expression [http://www.ncbi.nlm.nih.gov/pubmed/24335466?dopt=AbstractPlus] can cause Drug‐Induced Liver Injury (DILI) in the form of cholestatic liver injury. |
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=153
Overview
Subfamily ABCC contains thirteen members and nine of these transporters are referred to as Multidrug Resistance Proteins (MRPs). MRP proteins are found throughout nature and mediate many important functions. They are known to be involved in ion transport, toxin secretion, and signal transduction [http://www.ncbi.nlm.nih.gov/pubmed/11441126?dopt=AbstractPlus].
| Nomenclature | http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2594 | http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2746 | http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=786 |
| Systematic nomenclature | ABCC8 | – | – |
| Common abbreviation | SUR1 | SUR2 | MRP8 |
| HGNC, UniProt | https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:59, http://www.uniprot.org/uniprot/Q09428 | https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:60, http://www.uniprot.org/uniprot/O60706 | https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:14639, http://www.uniprot.org/uniprot/Q96J66 |
| Selective inhibitors | http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6841 (pIC50 7) [http://www.ncbi.nlm.nih.gov/pubmed/15380228?dopt=AbstractPlus] | – | – |
| 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) [http://www.ncbi.nlm.nih.gov/pubmed/22260657?dopt=AbstractPlus]. SUR2 (ABCC9) has also been identified [http://www.ncbi.nlm.nih.gov/pubmed/7502040?dopt=AbstractPlus]. 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 [http://www.ncbi.nlm.nih.gov/pubmed/10194514?dopt=AbstractPlus]. Co‐expression of Kir6.2 with SUR1, reconstitutes the ATP‐dependent K+ conductivity inhibited by the sulfonyureas [http://www.ncbi.nlm.nih.gov/pubmed/7502040?dopt=AbstractPlus]. | Associated with familial atrial fibrillation, Cantu syndrome and familial isolated dilated cardiomyopathy. | Single nucleotide polymorphisms distinguish wet vs. dry earwax (http://omim.org/entry/117800); an association between earwax allele and breast cancer risk is reported in Japanese but not European populations. |
Comments
ABCC7 (also known as http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=707, 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 http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=120 section of the Guide. ABCC8 (http://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000006071;r=11:17414432‐17498449, also known as SUR1, sulfonylurea receptor 1) and ABCC9 (http://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000069431;r=12:21950335‐22094336, also known as SUR2, sulfonylurea receptor 2) are unusual in that they lack transport capacity but regulate the activity of particular K+ channels (http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=74), conferring nucleotide sensitivity to these channels to generate the canonical KATP channels. ABCC13 (http://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000243064;r=21:15646120‐15735075) is a possible pseudogene.
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=154
Overview
Peroxisomes are indispensable organelles in higher eukaryotes. They are essential for the oxidation of a wide variety of metabolites, which include: saturated, monounsaturated and polyunsaturated fatty acids, branched‐chain fatty acids, bile acids and dicarboxylic acids [http://www.ncbi.nlm.nih.gov/pubmed/21488864?dopt=AbstractPlus]. However, the peroxisomal membrane forms an impermeable barrier to these metabolites. The mammalian peroxisomal membrane harbours three ATP‐binding cassette (ABC) half‐transporters, which act as homo‐ and/or heterodimers to transport these metabolites across the peroxisomal membrane.
| Nomenclature | http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=788 | http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=789 | http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=790 |
| Common abbreviation | ALDP | ALDR | PMP70 |
| HGNC, UniProt | https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:61, http://www.uniprot.org/uniprot/P33897 | https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:66, http://www.uniprot.org/uniprot/Q9UBJ2 | https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:67, http://www.uniprot.org/uniprot/P28288 |
| Comments | Transports coenzyme A esters of very long chain fatty acids [http://www.ncbi.nlm.nih.gov/pubmed/18757502?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/21145416?dopt=AbstractPlus]. Loss‐of‐function mutations in ABCD1 (mutation registry held by the Adrenoleukodystrophy database; https://adrenoleukodystrophy.info/) result in adrenoleukodystrophy (http://omim.org/entry/300100) [http://www.ncbi.nlm.nih.gov/pubmed/27312864?dopt=AbstractPlus]. | In vitro experiments indicate that ABCD2 has overlapping substrate specificity with ABCD1 towards saturated and monounsaturated very long‐chain fatty acids, albeit at much lower specificity. ABCD2 has affinity for the polyunsaturated fatty acids C22:6‐CoA and C24:6‐CoA. However, in vivo proof for its true function is still lacking. No disease has yet been linked to a deficiency of ABCD2. | Transports long‐chain dicarboxylic acids, branched‐chain fatty acids and C27 bile acids DHC‐CoA and THC‐CoA [http://www.ncbi.nlm.nih.gov/pubmed/25168382?dopt=AbstractPlus]. In mitochondrial fatty acid deficient cells and mice, ABCD3 accepts medium and long‐chain fatty acids |
Comments
ABCD4 (http://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000119688;r=14:74752126‐74769759, also known as PMP69, PXMP1‐L or P70R) is located at the lysosome and is involved in the transport of vitamin B12 (cobalamin) from lysosomes into the cytosol [http://www.ncbi.nlm.nih.gov/pubmed/22922874?dopt=AbstractPlus].
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=155
Overview
This family of ‘half‐transporters’ act as homo‐ or heterodimers; particularly ABCG5 and ABCG8 are thought to be obligate heterodimers. The ABCG5/ABCG heterodimer sterol transporter structure has been determined [http://www.ncbi.nlm.nih.gov/pubmed/27144356?dopt=AbstractPlus], suggesting an extensive intracellular nucleotide binding domain linked to the transmembrane domains by a fold in the primary sequence. The functional ABCG2 transporter appears to be a homodimer with structural similarities to the ABCG5/ABCG8 heterodimer [http://www.ncbi.nlm.nih.gov/pubmed/28554189?dopt=AbstractPlus].
Comments on ATP‐binding cassette transporter family
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 [http://www.ncbi.nlm.nih.gov/pubmed/16421098?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/19570978?dopt=AbstractPlus]: https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:69 (http://www.uniprot.org/uniprot/P61221, also known as OABP or 2′‐5′ oligoadenylate‐binding protein); https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:70 (http://www.uniprot.org/uniprot/Q8NE71, also known as ABC50 or TNF‐a‐stimulated ABC protein); https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:71 (http://www.uniprot.org/uniprot/Q9UG63, also known as iron‐inhibited ABC transporter 2) and https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:72 (http://www.uniprot.org/uniprot/Q9NUQ8).
Further reading on ATP‐binding cassette transporter family
Baker A et al. (2015) Peroxisomal ABC transporters: functions and mechanism. Biochem. Soc. Trans. 43: 959‐65 https://www.ncbi.nlm.nih.gov/pubmed/26517910?dopt=AbstractPlus
Beis K. (2015) Structural basis for the mechanism of ABC transporters. Biochem. Soc. Trans. 43: 889‐93 https://www.ncbi.nlm.nih.gov/pubmed/26517899?dopt=AbstractPlus
Chen Z et al. (2016) Mammalian drug efflux transporters of the ATP binding cassette (ABC) family in multidrug resistance: A review of the past decade. Cancer Lett. 370: 153‐64 https://www.ncbi.nlm.nih.gov/pubmed/26499806?dopt=AbstractPlus
Kemp S et al. (2011) Mammalian peroxisomal ABC transporters: from endogenous substrates to pathology and clinical significance. Br. J. Pharmacol. 164: 1753‐66 https://www.ncbi.nlm.nih.gov/pubmed/21488864?dopt=AbstractPlus
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 https://www.ncbi.nlm.nih.gov/pubmed/21175590?dopt=AbstractPlus
Kloudova A et al. (2017) The Role of Oxysterols in Human Cancer. Trends Endocrinol. Metab. 28: 485‐496 https://www.ncbi.nlm.nih.gov/pubmed/28410994?dopt=AbstractPlus
López‐Marqués RL et al. (2015) Structure and mechanism of ATP‐dependent phospholipid transporters. Biochim. Biophys. Acta 1850: 461‐475 https://www.ncbi.nlm.nih.gov/pubmed/24746984?dopt=AbstractPlus
Neul C etal. (2016) Impact of Membrane Drug Transporters on Resistance to Small‐Molecule Tyrosine Kinase Inhibitors. Trends Pharmacol. Sci. 37: 904‐932 https://www.ncbi.nlm.nih.gov/pubmed/27659854?dopt=AbstractPlus
Peña‐Solórzano D et al. (2017) ABCG2/BCRP: Specific and Nonspecific Modulators. Med Res Rev 37: 987‐1050 https://www.ncbi.nlm.nih.gov/pubmed/28005280?dopt=AbstractPlus
Robey RW et al. (2018) Revisiting the role of ABC transporters in multidrug‐resistant cancer. Nat Rev Cancer 18: 452‐464 [https://www.ncbi.nlm.nih.gov/pubmed/29643473]
Vauthier V et al. (2017) Targeted pharmacotherapies for defective ABC transporters. Biochem. Pharmacol. 136: 1‐11 https://www.ncbi.nlm.nih.gov/pubmed/28245962?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=137
Overview
The F‐type (ATP synthase) and the V‐type (vacuolar or vesicular proton pump) ATPases, although having distinct sub‐cellular 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 http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1713 synthesis or hydrolysis to proton transport. Both the F‐type and V‐type ATPases have been assigned enzyme commission number http://www.genome.jp/kegg‐bin/search_brite?option=‐a&search_string=3.6.3.14
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=156
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 http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1713, although it is also possible for the enzyme to function as an AT‐Pase. The ATP5O subunit (oligomycin sensitivity‐conferring protein, https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:850, (http://www.uniprot.org/uniprot/P48047)), acts as a connector between F1 and F0 motors.
The F1 motor, responsible for http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1713 turnover, has the subunit composition α3β3γδε.
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.
Information on members of this family may be found in the http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=156.
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=157
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, for http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1713 turnover, has subunits with a of A‐H.
TheV0 motor, responsible for ion translocation, has six subunits (a‐e).
Information on members of this family may be found in the http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=157.
Further reading on F‐type and V‐type ATPases
Brandt K et al. (2015) Hybrid rotors in F1F(o) ATP synthases: subunit composition, distribution, and physiological significance. Biol. Chem. 396: 1031–42 https://www.ncbi.nlm.nih.gov/pubmed/25838297?dopt=AbstractPlus
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. 119: 94–102 https://www.ncbi.nlm.nih.gov/pubmed/26140992?dopt=AbstractPlus
Marshansky V et al. (2014) Eukaryotic V‐ATPase: novel structural findings and functional insights. Biochim. Biophys. Acta 1837: 857–79 https://www.ncbi.nlm.nih.gov/pubmed/24508215?dopt=AbstractPlus
Noji H et al. (2017) Catalytic robustness and torque generation of the F_1‐ATPase. Biophys Rev 9: 103–118 https://www.ncbi.nlm.nih.gov/pubmed/28424741?dopt=AbstractPlus
Okuno D et al. (2013) Single‐molecule analysis of the rotation of F_1‐ATPase under high hydrostatic pressure. Biophys. J. 105: 1635–42 https://www.ncbi.nlm.nih.gov/pubmed/24094404?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=138
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.
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=158
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. Additional protein partners known as FXYD proteins (e.g. https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:4026, http://www.uniprot.org/uniprot/P54710) appear to associate with and regulate the activity of the pump.
Information on members of this family may be found in the http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=158.
Comments
Na+/K+‐ATPases are inhibited by http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4826 and cardiac glycosides, such as http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4726, as well as potentially endogenous cardiotonic steroids [http://www.ncbi.nlm.nih.gov/pubmed/19325075?dopt=AbstractPlus].
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=159
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.
Information on members of this family may be found in the http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=159.
Comments
The fungal toxin http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4672 has been described to activate SERCA in kidney microsomes [http://www.ncbi.nlm.nih.gov/pubmed/1417961?dopt=AbstractPlus]. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5350 [http://www.ncbi.nlm.nih.gov/pubmed/2530215?dopt=AbstractPlus], http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5351 [http://www.ncbi.nlm.nih.gov/pubmed/1832668?dopt=AbstractPlus] and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5486are widely employed to block SERCA. Thapsigargin has also been described to block the TRPV1 vanilloid receptor [http://www.ncbi.nlm.nih.gov/pubmed/12054538?dopt=AbstractPlus].
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 [http://www.ncbi.nlm.nih.gov/pubmed/10615129?dopt=AbstractPlus].
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=160
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 [http://www.ncbi.nlm.nih.gov/pubmed/16525125?dopt=AbstractPlus].
Information on members of this family may be found in the http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=160.
Comments
The gastric H+/K+‐ATPase is inhibited by proton pump inhibitors used for treating excessive gastric acid secretion, including http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5487 and a metabolite of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5488.
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=161
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. https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:798, http://www.uniprot.org/uniprot/O00244).
Information on members of this family may be found in the http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=161.
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=162
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.
Information on members of this family may be found in the http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=162.
Comments
Loss‐of‐functionmutations 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 https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:24215 (http://www.uniprot.org/uniprot/Q9HD20), https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:30213 (http://www.uniprot.org/uniprot/Q9NQ11), https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:24113 (http://www.uniprot.org/uniprot/Q9H7F0), https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:25422 (http://www.uniprot.org/uniprot/Q4VNC1) and https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:31789 (http://www.uniprot.org/uniprot/Q4VNC0).
Further reading on P‐type ATPases
Aperia A et al. (2016) Na+‐K+‐ATPase, a new class of plasma membrane receptors. Am. J. Physiol., Cell Physiol. 310: C491–5 https://www.ncbi.nlm.nih.gov/pubmed/26791490?dopt=AbstractPlus
Brini M et al. (2017) The plasma membrane calcium pumps: focus on the role in (neuro)pathology. Biochem. Biophys. Res. Commun. 483: 1116–1124 https://www.ncbi.nlm.nih.gov/pubmed/27480928?dopt=AbstractPlus
Bruce JIE. (2018) Metabolic regulation of the PMCA: Role in cell death and survival. Cell Calcium 69: 28–36 https://www.ncbi.nlm.nih.gov/pubmed/27553475?dopt=AbstractPlus
Diederich M et al. (2017) Cardiac glycosides: From molecular targets to immunogenic cell death. Biochem. Pharmacol. 125: 1–11 https://www.ncbi.nlm.nih.gov/pubmed/27553475?dopt=AbstractPlus
Dubois C et al. (2016) The calcium‐signaling toolkit: Updates needed. Biochim. Biophys. Acta 1863: 1337–43 https://www.ncbi.nlm.nih.gov/pubmed/26658643?dopt=AbstractPlus
Krebs J. (2015) The plethora of PMCA isoforms: Alternative splicing and differential expression. Biochim. Biophys. Acta 1853: 2018–24 https://www.ncbi.nlm.nih.gov/pubmed/25535949?dopt=AbstractPlus
Little R et al. (2016) Plasma membrane calcium ATPases (PMCAs) as potential targets for the treatment of essential hypertension. Pharmacol. Ther. 159: 23–34 https://www.ncbi.nlm.nih.gov/pubmed/26820758?dopt=AbstractPlus
López‐Marqués RL et al. (2015) Structure and mechanism of ATP‐dependent phospholipid transporters. Biochim. Biophys. Acta 1850: 461–475 https://www.ncbi.nlm.nih.gov/pubmed/24746984?dopt=AbstractPlus
Migocka M. (2015) Copper‐transporting ATPases: The evolutionarily conserved machineries for balancing copper in living systems. IUBMB Life 67: 737–45 https://www.ncbi.nlm.nih.gov/pubmed/26422816?dopt=AbstractPlus
Padányi R et al. (2016) Multifaceted plasmamembrane Ca(2+) pumps: From structure to intracellular Ca(2+) handling and cancer. Biochim. Biophys. Acta 1863: 1351–63 https://www.ncbi.nlm.nih.gov/pubmed/26707182?dopt=AbstractPlus
Pomorski TG et al. (2016) Lipid somersaults: Uncovering the mechanisms of protein‐mediated lipid flipping. Prog. Lipid Res. 64: 69–84 https://www.ncbi.nlm.nih.gov/pubmed/27528189?dopt=AbstractPlus
Retamales‐Ortega R et al. (2016) P2C‐Type ATPases and Their Regulation. Mol. Neurobiol. 53: 1343–54 https://www.ncbi.nlm.nih.gov/pubmed/25631710?dopt=AbstractPlus
Tadini‐Buoninsegni F et al. (2017) Mechanisms of charge transfer in human copper ATPases ATP7A and ATP7B. IUBMB Life 69: 218–225 https://www.ncbi.nlm.nih.gov/pubmed/28164426?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=863
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 TMdomain 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.
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=139
Overview
The SLC1 family of sodium dependent transporters includes the plasma membrane located glutamate transporters and the neutral amino acid transporters ASCT1 and ASCT2 [http://www.ncbi.nlm.nih.gov/pubmed/8103691?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/17088867?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/14530974?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/14612154?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/9790568?dopt=AbstractPlus].
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=163
Overview
Glutamate transporters present the unusual structural motif of 8TM segments and 2 re‐entrant loops [http://www.ncbi.nlm.nih.gov/pubmed/10734120?dopt=AbstractPlus]. 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 [http://www.ncbi.nlm.nih.gov/pubmed/17230192?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/19924125?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/15483603?dopt=AbstractPlus] reviewed by [http://www.ncbi.nlm.nih.gov/pubmed/20708631?dopt=AbstractPlus]). This structural data is in agreementwith the proposed quaternary structure for EAAT2 [http://www.ncbi.nlm.nih.gov/pubmed/15265858?dopt=AbstractPlus] and several functional studies that propose the monomer is the functional unit [http://www.ncbi.nlm.nih.gov/pubmed/16128593?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/17360917?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/17360916?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/14982939?dopt=AbstractPlus]. Recent evidence suggests that EAAT3 and EAAT4 may assemble as heterotrimers [http://www.ncbi.nlm.nih.gov/pubmed/21127051?dopt=AbstractPlus]. 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 http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=138 that maintains the ion gradients that drive transport has been demonstrated to co‐assemble with EAAT1 and EAAT2 [http://www.ncbi.nlm.nih.gov/pubmed/19553454?dopt=AbstractPlus]. Recent evidence supports altered glutamate transport and novel roles in brain for splice variants of EAAT1 and EAAT2 [http://www.ncbi.nlm.nih.gov/pubmed/20688910?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/20883814?dopt=AbstractPlus]. Three patients with dicarboxylic aminoaciduria (DA) were recently found to have loss‐of‐function mutations in EAAT3 [http://www.ncbi.nlm.nih.gov/pubmed/21123949?dopt=AbstractPlus]. 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 fromadministration of ß‐lactam antibiotics (e.g. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5326) is neuroprotective and occurs through NF‐?B‐mediated EAAT2 promoter activation [http://www.ncbi.nlm.nih.gov/pubmed/16274998?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/18326497?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/15635412?dopt=AbstractPlus] reviewed by [http://www.ncbi.nlm.nih.gov/pubmed/21792905?dopt=AbstractPlus]). http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=86 activation (e.g. by http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1056) also leads to enhanced expression of EAAT though promoter activation [http://www.ncbi.nlm.nih.gov/pubmed/17213861?dopt=AbstractPlus]. In addition, several translational activators of EAAT2 have recently been described [http://www.ncbi.nlm.nih.gov/pubmed/20508255?dopt=AbstractPlus] along with treatments that increase the surface expression of EAAT2 (e.g. [http://www.ncbi.nlm.nih.gov/pubmed/21309758?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/21426345?dopt=AbstractPlus]), or prevent its down‐regulation (e.g. [http://www.ncbi.nlm.nih.gov/pubmed/21730107?dopt=AbstractPlus]). A thermodynamically uncoupled Cl‐ flux, activated by Na+ and glutamate [http://www.ncbi.nlm.nih.gov/pubmed/15834685?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/14612154?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/21572047?dopt=AbstractPlus] (Na+ and aspartate in the case of GltPh [http://www.ncbi.nlm.nih.gov/pubmed/21730107?dopt=AbstractPlus]), is sufficiently large, in the instances of EAAT4 and EAAT5, to influence neuronal excitability [http://www.ncbi.nlm.nih.gov/pubmed/17908688?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/17041592?dopt=AbstractPlus]. 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 [http://www.ncbi.nlm.nih.gov/pubmed/21641307?dopt=AbstractPlus].
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 [http://www.ncbi.nlm.nih.gov/pubmed/11299317?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/11677257?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/9463476?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/9145919?dopt=AbstractPlus]. KB (or Ki) values derived in uptake assays are generally higher (e.g. [http://www.ncbi.nlm.nih.gov/pubmed/9463476?dopt=AbstractPlus]). In addition to acting as a poorly transportable inhibitor of EAAT2, (2S,4R)‐4‐methylglutamate, also known as http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4317, is a competitive substrate for EAAT1 (KM = 54μM; [http://www.ncbi.nlm.nih.gov/pubmed/19074430?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/9145919?dopt=AbstractPlus]) and additionally is a potent kainate receptor agonist [http://www.ncbi.nlm.nih.gov/pubmed/8996224?dopt=AbstractPlus] which renders the compound unsuitable for autoradiographic localisation of EAATs [http://www.ncbi.nlm.nih.gov/pubmed/17590480?dopt=AbstractPlus]. Similarly, at concentrations that inhibit EAAT2, dihydrokainate binds to kainate receptors [http://www.ncbi.nlm.nih.gov/pubmed/9463476?dopt=AbstractPlus]. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5327 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4531 are both non‐substrate inhibitors with a preference for EAAT2 over EAAT3 and EAAT1 [http://www.ncbi.nlm.nih.gov/pubmed/14517179?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/16014807?dopt=AbstractPlus]. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4626 is a non‐substrate inhibitor with modest selectivity for EAAT3 over EAAT1 (>10‐fold) and EAAT2 (5‐fold) [126, http://www.ncbi.nlm.nih.gov/pubmed/16368269?dopt=AbstractPlus]. Analogously, L‐β‐threo‐benzyl‐aspartate (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4625) is a competitive nonsubstrate inhibitor that preferentially blocks EAAT3 versus EAAT1, or EAAT2 [http://www.ncbi.nlm.nih.gov/pubmed/16183084?dopt=AbstractPlus]. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4075 demonstrates low affinity binding (KD≅6.0 μM) to EAAT1 and EAAT2 in rat brain homogenates [http://www.ncbi.nlm.nih.gov/pubmed/11389172?dopt=AbstractPlus] and EAAT1 in murine astrocyte membranes [http://www.ncbi.nlm.nih.gov/pubmed/14994336?dopt=AbstractPlus], whereas http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4492 binds with high affinity to all EAATs other than EAAT3 [http://www.ncbi.nlm.nih.gov/pubmed/17047096?dopt=AbstractPlus]. The novel isoxazole derivative http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5328 may interact at the same site as TBOA and preferentially inhibit reverse transport of glutamate [http://www.ncbi.nlm.nih.gov/pubmed/18451317?dopt=AbstractPlus]. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4573 induces substrate‐like currents at EAAT4, but does not elicit heteroexchange of [3H]‐aspartate in synaptosome preparations, inconsistentwith the behaviour of a substrate inhibitor [http://www.ncbi.nlm.nih.gov/pubmed/11299317?dopt=AbstractPlus]. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5352, 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 [http://www.ncbi.nlm.nih.gov/pubmed/17646426?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/12890709?dopt=AbstractPlus]. In addition to the agents listed in the table, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4497 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4516 act as non‐selective competitive substrate inhibitors of all EAATs. Zn2+ and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2391 are putative endogenous modulators of EAATs with actions that differ across transporter subtypes (reviewed by [http://www.ncbi.nlm.nih.gov/pubmed/15324920?dopt=AbstractPlus]).
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=164
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 [http://www.ncbi.nlm.nih.gov/pubmed/8101838?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/8662767?dopt=AbstractPlus]. ASCT1 and ASCT2 also exhibit thermodynamically uncoupled chloride channel activity associated with substrate transport [http://www.ncbi.nlm.nih.gov/pubmed/10698697?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/8910405?dopt=AbstractPlus]. Whereas EAATs counter‐transport K+ (see above) ASCTs do not and their function is independent of the intracellular concentration of K+ [http://www.ncbi.nlm.nih.gov/pubmed/8910405?dopt=AbstractPlus].
Comments
The substrate specificity of ASCT1 may extend to http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3314 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4704 [http://www.ncbi.nlm.nih.gov/pubmed/14502423?dopt=AbstractPlus]. At low pH (5.5) both ASCT1 and ASCT2 are able to exchange acidic amino acids such as http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5329 and glutamate [http://www.ncbi.nlm.nih.gov/pubmed/8603078?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/8662767?dopt=AbstractPlus]. In addition to the inhibitors tabulated above, HgCl2, methylmercury and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5331, at low micromolar concentrations, non‐competitively inhibit ASCT2 by covalent modificiation of cysteine residues [http://www.ncbi.nlm.nih.gov/pubmed/20599776?dopt=AbstractPlus].
Further reading on SLC1 family of amino acid transporters
Beart PM et al. (2007) Transporters for L‐glutamate: an update on their molecular pharmacology and pathological involvement. Br. J. Pharmacol. 150: 5–17 https://www.ncbi.nlm.nih.gov/pubmed/17088867?dopt=AbstractPlus
Bjrn‐Yoshimoto WE et al. (2016) The importance of the excitatory amino acid transporter 3 (EAAT3). Neurochem. Int. 98: 4–18 https://www.ncbi.nlm.nih.gov/pubmed/27233497?dopt=AbstractPlus
Fahlke C et al. (2016) Molecular physiology of EAAT anion channels. Pflugers Arch. 468: 491–502 https://www.ncbi.nlm.nih.gov/pubmed/26687113?dopt=AbstractPlus
Fontana AC. (2015) Current approaches to enhance glutamate transporter function and expression. J. Neurochem. 134: 982–1007 https://www.ncbi.nlm.nih.gov/pubmed/26096891?dopt=AbstractPlus
Grewer C et al. (2014) SLC1 glutamate transporters. Pflugers Arch. 466: 3–24 https://www.ncbi.nlm.nih.gov/pubmed/24240778?dopt=AbstractPlus
Jensen AA et al. (2015) Excitatory amino acid transporters: recent insights into molecular mechanisms, novel modes of modulation and new therapeutic possibilities. Curr Opin Pharmacol 20: 116–23 https://www.ncbi.nlm.nih.gov/pubmed/25466154?dopt=AbstractPlus
Kanai Y et al. (2013) The SLC1 high‐affinity glutamate and neutral amino acid transporter family. Mol. Aspects Med. 34: 108–20 https://www.ncbi.nlm.nih.gov/pubmed/23506861?dopt=AbstractPlus
Takahashi K et al. (2015) Glutamate transporter EAAT2: regulation, function, and potential as a therapeutic target for neurological and psychiatric disease. Cell. Mol. Life Sci. 72: 3489–506 https://www.ncbi.nlm.nih.gov/pubmed/26033496?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=140
Overview
The SLC2 family transports http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4536, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4654, inositol (e.g. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4495) 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.
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=165
Overview
Class I transporters are able to transport http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4536, but not http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4654, in the direction of the concentration gradient and may be inhibited non‐selectively by http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4285 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5334. 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 [http://www.ncbi.nlm.nih.gov/pubmed/12504846?dopt=AbstractPlus].
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=166
Overview
Class II transporters transport http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4654 and appear to be insensitive to http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5334. Class II transporters appear to be predominantly intracellularly located.
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=167
Overview
Proton‐coupled inositol transporters are expressed predominantly in the brain and can be inhibited by http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4285 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5334 [http://www.ncbi.nlm.nih.gov/pubmed/12135767?dopt=AbstractPlus].
Further reading on SLC2 family of hexose and sugar alcohol transporters
Augustin R. (2010) The protein family of glucose transport facilitators: It's not only about glucose after all. IUBMB Life 62: 315–33 https://www.ncbi.nlm.nih.gov/pubmed/20209635?dopt=AbstractPlus
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 https://www.ncbi.nlm.nih.gov/pubmed/24598362?dopt=AbstractPlus
Leney SE et al. (2009) Themolecular basis of insulin‐stimulated glucose uptake: signalling, trafficking and potential drug targets. J. Endocrinol. 203: 1–18 https://www.ncbi.nlm.nih.gov/pubmed/19389739?dopt=AbstractPlus
Mueckler M et al. (2013) The SLC2 (GLUT) family of membrane transporters. Mol. Aspects Med. 34: 121‐38 https://www.ncbi.nlm.nih.gov/pubmed/23506862?dopt=AbstractPlus
Uldry M et al. (2004) The SLC2 family of facilitated hexose and polyol transporters. Pflugers Arch. 447: 480‐9 https://www.ncbi.nlm.nih.gov/pubmed/12750891?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=141
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).
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=168
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.
Information on members of this family may be found in the http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=168.
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=169
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 http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5335.
Comments
CAT4 appears to be non‐functional in heterologous expression [http://www.ncbi.nlm.nih.gov/pubmed/12049641?dopt=AbstractPlus], 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 http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4841, 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 (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=721, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=724, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=725) amino acids independent of sodium and neutral (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3312, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3311, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4814, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=723) amino acids in a partially sodium‐dependent manner. These transporters are http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5335‐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 (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=721, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=724 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=725).
Asc‐1 appears to heterodimerize with 4F2hc to allow the transport of small neutral amino acids (such as http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=720, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=726, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4785, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=723 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=727), as well as http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4171, 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 http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5413 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1369.
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 on SLC3 and SLC7 families of heteromeric amino acid transporters (HATs)
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 https://www.ncbi.nlm.nih.gov/pubmed/25855379?dopt=AbstractPlus
Fotiadis D et al. (2013) The SLC3 and SLC7 families of amino acid transporters. Mol. Aspects Med. 34: 139–58 https://www.ncbi.nlm.nih.gov/pubmed/23506863?dopt=AbstractPlus
Palacín M et al. (2004) The ancillary proteins of HATs: SLC3 family of amino acid transporters. Pflugers Arch. 447: 490–4 https://www.ncbi.nlm.nih.gov/pubmed/14770309?dopt=AbstractPlus
Palacín M et al. (2005) The genetics of heteromeric amino acid transporters. Physiology (Bethesda) 20: 112–24 https://www.ncbi.nlm.nih.gov/pubmed/15772300?dopt=AbstractPlus
Verrey F et al. (2004) CATs and HATs: the SLC7 family of amino acid transporters. Pflugers Arch. 447: 532–42 https://www.ncbi.nlm.nih.gov/pubmed/14770310?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=142
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 dioxidemovement, 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.
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=170
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=171
Further reading on SLC4 family of bicarbonate transporters
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 [https://www.ncbi.nlm.nih.gov/pubmed/20884330?dopt=AbstractPlus]
Parker MD et al. (2013) The divergence, actions, roles, and relatives of sodium‐coupled bicarbonate transporters. Physiol. Rev. 93: 803‐959 [https://www.ncbi.nlm.nih.gov/pubmed/23589833?dopt=AbstractPlus]
Reithmeier RA et al. (2016) Band 3, the human red cell chloride/bicarbonate anion exchanger (AE1, SLC4A1), in a structural context. Biochim. Biophys. Acta 1858: 1507‐32 [https://www.ncbi.nlm.nih.gov/pubmed/27058983?dopt=AbstractPlus]
Romero MF et al. (2013) The SLC4 family of bicarbonate (HCO_3‐) transporters. Mol. Aspects Med. 34: 159‐82 [https://www.ncbi.nlm.nih.gov/pubmed/23506864?dopt=AbstractPlus]
Thornell IM et al. (2015) Regulators of Slc4 bicarbonate transporter activity. Front Physiol 6: 166 [https://www.ncbi.nlm.nih.gov/pubmed/26124722?dopt=AbstractPlus]
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=143
Overview
The SLC5 family of sodium‐dependent glucose transporters includes, in mammals, the Na+/substrate co‐transporters for glucose (e.g. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4551), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4536, monocarboxylates, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4495 and I‐ [http://www.ncbi.nlm.nih.gov/pubmed/14993474?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/18446519?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/21527736?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/12748858?dopt=AbstractPlus]. 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 [http://www.ncbi.nlm.nih.gov/pubmed/19631523?dopt=AbstractPlus].
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=173
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 http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4757, a natural dihydrocholine glucoside, that exhibits modest selectivity towards SGLT2 (see [http://www.ncbi.nlm.nih.gov/pubmed/21527736?dopt=AbstractPlus] for an extensive review). SGLT1 is predominantly expressed in the small intestine, mediating the absorption of glucose (e.g. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4536), 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 [http://www.ncbi.nlm.nih.gov/pubmed/13130073?dopt=AbstractPlus].
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 [http://www.ncbi.nlm.nih.gov/pubmed/21527736?dopt=AbstractPlus] for a detailed quantification). Although SGLT1 and SGLT2 have been described as high‐ and lowaffinity sodium glucose co‐transporters, respectively, recent work suggests that they have a similar affinity for glucose under physiological conditions [http://www.ncbi.nlm.nih.gov/pubmed/20980548?dopt=AbstractPlus]. Selective blockers of SGLT2, and thus blocking 50% of renal glucose reabsorption, are in development for the treatment of diabetes (e.g. [http://www.ncbi.nlm.nih.gov/pubmed/20508640?dopt=AbstractPlus]).
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=172
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 [http://www.ncbi.nlm.nih.gov/pubmed/19186169?dopt=AbstractPlus]. Through recapture of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4551 generated by the hydrolysis of ACh by http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=294sterase, CHT serves to maintain acetylcholine synthesis within the presynaptic terminal [http://www.ncbi.nlm.nih.gov/pubmed/14993474?dopt=AbstractPlus]. 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 [http://www.ncbi.nlm.nih.gov/pubmed/15173594?dopt=AbstractPlus]. 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 [http://www.ncbi.nlm.nih.gov/pubmed/15715662?dopt=AbstractPlus].
| Nomenclature | http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=914 |
| Systematic nomenclature | SLC5A7 |
| HGNC, UniProt | https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:14025, http://www.uniprot.org/uniprot/Q9GZV3 |
| Substrates | http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4760 |
| Endogenous substrates | http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4551 |
| Stoichiometry | Na+ : choline (variable stoichimetry); modulated by extracellular Cl‐ [http://www.ncbi.nlm.nih.gov/pubmed/17005849?dopt=AbstractPlus] |
| Selective inhibitors | http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4494 (pK i 7–8) [http://www.ncbi.nlm.nih.gov/pubmed/12675135?dopt=AbstractPlus] |
| Labelled ligands | http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4493 (pK d 8.2–8.4) |
Comments
Ki and KD values for http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4494 listed in the table are for human CHT expressed in Xenopus laevis oocytes [http://www.ncbi.nlm.nih.gov/pubmed/11068039?dopt=AbstractPlus], or COS‐7 cells [http://www.ncbi.nlm.nih.gov/pubmed/11027560?dopt=AbstractPlus]. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5502 is a substrate for CHT that causes covalent modification and irreversible inactivation of the transporter. Several exogenous substances (e.g. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4760) that are substrates for CHT act as precursors to cholinergic false transmitters.
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=174
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 (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2634) and thyroxine (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2635) [http://www.ncbi.nlm.nih.gov/pubmed/19196800?dopt=AbstractPlus]. 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 http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4787 (vitamin H) and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4668 (vitamin B5) uptake in humans [http://www.ncbi.nlm.nih.gov/pubmed/19056639?dopt=AbstractPlus]. SMVT located in kidney proximal tubule epithelial cells mediates the reabsorption of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4787 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4668. 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 [http://www.ncbi.nlm.nih.gov/pubmed/18446519?dopt=AbstractPlus]. 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 [http://www.ncbi.nlm.nih.gov/pubmed/18446519?dopt=AbstractPlus]. SMCT1 is a high‐affinity transporter whereas SMCT2 is a lowaffinity transporter. The physiological substrates for SMCT1 and SMCT2 are lactate (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2932 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2934), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4809, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1062, and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1588 in non‐colonic tissues such as the kidney. SMCT1 is also likely to be the principal transporter for the absorption of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1588 (vitamin B3) in the intestine and kidney [http://www.ncbi.nlm.nih.gov/pubmed/15651982?dopt=AbstractPlus]. In the small intestine and colon, the physiological substrates for these transporters are http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1588 and the shortchain fatty acids http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1058, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1062, and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1059 that are produced by bacterial fermentation of dietary fiber [http://www.ncbi.nlm.nih.gov/pubmed/14966140?dopt=AbstractPlus]. 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 [http://www.ncbi.nlm.nih.gov/pubmed/16873376?dopt=AbstractPlus]. SMCT1 also functions as a tumour suppressor in the colon as well as in various other non‐colonic tissues [http://www.ncbi.nlm.nih.gov/pubmed/18992769?dopt=AbstractPlus]. The tumour‐suppressive function of SMCT1 is based on its ability to transport http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4809, an inhibitor of histone deacetylases, into cells in non‐colonic tissues [http://www.ncbi.nlm.nih.gov/pubmed/17178845?dopt=AbstractPlus]; in the colon, the ability of SMCT1 to transport http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1059 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1062, also inhibitors of histone deacetylases, underlies the tumour‐suppressive function of this transporter [http://www.ncbi.nlm.nih.gov/pubmed/18446519?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/18992769?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/16375929?dopt=AbstractPlus]. The ability of SMCT1 to promote histone acetylase inhibition through accumulation of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1059 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1062 in immune cells is also responsible for suppression of dendritic cell development in the colon [http://www.ncbi.nlm.nih.gov/pubmed/20601425?dopt=AbstractPlus].
Comments
I‐, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4524, thiocyanate and NO3 ‐ are competitive substrate inhibitors of NIS [http://www.ncbi.nlm.nih.gov/pubmed/18077370?dopt=AbstractPlus]. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4822 appears to act as a competitive substrate inhibitor of SMVT [http://www.ncbi.nlm.nih.gov/pubmed/10329687?dopt=AbstractPlus] and the anticonvulsant drugs http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5338 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5339 competitively block the transport of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4787 by brush border vesicles prepared from human intestine [http://www.ncbi.nlm.nih.gov/pubmed/2911998?dopt=AbstractPlus].
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=175
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 [http://www.ncbi.nlm.nih.gov/pubmed/15181167?dopt=AbstractPlus]. In the nephron, SMIT1 mediates http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4495 uptake as a ‘compatible osmolyte’ when inner medullary tubules are exposed to increases in extracellular osmolality, whilst SMIT2 mediates the reabsorption of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4495 from the filtrate. In some species (e.g. rat, but not rabbit) apically located SMIT2 is responsible for the uptake of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4495 from the intestinal lumen [http://www.ncbi.nlm.nih.gov/pubmed/17932225?dopt=AbstractPlus].
Comments
The data tabulated are those for dog SMIT1 and rabbit SMIT2. SMIT2 transports http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4645, but SMIT1 does not. In addition, whereas SMIT1 transports both http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4724 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4720 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4722 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4721, SMIT2 transports only the D‐isomers of these sugars [http://www.ncbi.nlm.nih.gov/pubmed/12133831?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/7537337?dopt=AbstractPlus]. Thus the substrate specificities of SMIT1 (for http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4721) and SMIT2 (for http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4645) allow discrimination between the two SMITs. Human SMIT2 appears not to transport glucose [http://www.ncbi.nlm.nih.gov/pubmed/19032932?dopt=AbstractPlus].
Further reading on SLC5 family of sodium‐dependent glucose transporters
DeFronzo RA et al. (2017) Renal, metabolic and cardiovascular considerations of SGLT2 inhibition. Nat Rev Nephrol 13: 11‐26 https://www.ncbi.nlm.nih.gov/pubmed/27941935?dopt=AbstractPlus
Koepsell H. (2017) The Na+‐D‐glucose cotransporters SGLT1 and SGLT2 are targets for the treatment of diabetes and cancer. Pharmacol. Ther. 170: 148‐165 https://www.ncbi.nlm.nih.gov/pubmed/27773781?dopt=AbstractPlus
Lehmann A et al. (2016) Intestinal SGLT1 inmetabolic health and disease. Am. J. Physiol. Gastrointest. Liver Physiol. 310: G887‐98 https://www.ncbi.nlm.nih.gov/pubmed/27012770?dopt=AbstractPlus
Wright EM. (2013) Glucose transport families SLC5 and SLC50. Mol. Aspects Med. 34: 183‐96 https://www.ncbi.nlm.nih.gov/pubmed/23506865?dopt=AbstractPlus
Wright EM et al. (2011) Biology of human sodium glucose transporters. Physiol. Rev. 91: 733‐94 https://www.ncbi.nlm.nih.gov/pubmed/21527736?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=144
Overview
Members of the solute carrier family 6 (SLC6) of sodium‐ and (sometimes chloride‐) dependent neurotransmitter transporters [http://www.ncbi.nlm.nih.gov/pubmed/16540203?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/12719981?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/21752877?dopt=AbstractPlus] are primarily plasma membrane located and may be divided into four subfamilies that transport monoamines, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1067, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=727 and neutral amino acids, plus the related bacterial NSS transporters [http://www.ncbi.nlm.nih.gov/pubmed/19022853?dopt=AbstractPlus]. 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 [http://www.ncbi.nlm.nih.gov/pubmed/16041361?dopt=AbstractPlus] and in several other transporter families structurally related to LeuT [http://www.ncbi.nlm.nih.gov/pubmed/19996368?dopt=AbstractPlus].
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=176
Overview
Monoamine neurotransmission is limited by perisynaptic transporters. Presynapticmonoamine transporters allow recycling of synaptically released http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=484, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=940 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5.
Comments
http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5409 labels all three monoamine transporters (NET, DAT and SERT) with affinities between 0.5 and 5 nM. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2286 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 [http://www.ncbi.nlm.nih.gov/pubmed/17687333?dopt=AbstractPlus].
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=177
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 http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1067 are sufficient to sustain tonic inhibition mediated by high affinity GABAA receptors in certain neuronal populations [http://www.ncbi.nlm.nih.gov/pubmed/15111008?dopt=AbstractPlus]. 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 [http://www.ncbi.nlm.nih.gov/pubmed/20026354?dopt=AbstractPlus]. 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 [http://www.ncbi.nlm.nih.gov/pubmed/12719981?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/16734743?dopt=AbstractPlus]. CT1, which transports http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4496, has a ubiquitous expression pattern, often co‐localizing with creatine kinase [http://www.ncbi.nlm.nih.gov/pubmed/12719981?dopt=AbstractPlus].
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 [http://www.ncbi.nlm.nih.gov/pubmed/19275529?dopt=AbstractPlus]. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4677 is only weakly selective for GAT 2 and GAT3, with IC50 values in the range 22 to >30 μM at GAT1 and BGT1, whereas http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4610 has at least an order of magnitude selectivity for BGT1 [see [http://www.ncbi.nlm.nih.gov/pubmed/17175818?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/15451399?dopt=AbstractPlus] for reviews]. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5489 is a recently described compound that displays 20‐fold selectivity for GAT3 over GAT1 [http://www.ncbi.nlm.nih.gov/pubmed/16766089?dopt=AbstractPlus]. In addition to the inhibitors listed, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5490 is a moderately potent, though non‐selective, inhibitor of all cloned GABA transporters (IC50 = 26‐46 μM; [http://www.ncbi.nlm.nih.gov/pubmed/8057281?dopt=AbstractPlus]). Diaryloxime and diarylvinyl ether derivatives of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4564 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4691 that potently inhibit the uptake of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5410 into rat synaptosomes have been described [http://www.ncbi.nlm.nih.gov/pubmed/10479278?dopt=AbstractPlus]. Several derivatives of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5418 (e.g. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5419 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5420) demonstrate selectivity as blockers of astroglial, versus neuronal, uptake of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1067 [see [http://www.ncbi.nlm.nih.gov/pubmed/17175818?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/21428813?dopt=AbstractPlus] for reviews]. GAT3 is inhibited by physiologically relevant concentrations of Zn2+ [http://www.ncbi.nlm.nih.gov/pubmed/15829583?dopt=AbstractPlus]. Taut transports http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1067, 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 [http://www.ncbi.nlm.nih.gov/pubmed/17400549?dopt=AbstractPlus]. Although inhibitors of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4496 transport by CT1 (e.g. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4707, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5491, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5492) are known (e.g. [http://www.ncbi.nlm.nih.gov/pubmed/9882430?dopt=AbstractPlus]) they insufficiently characterized to be included in the table.
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=178
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 [http://www.ncbi.nlm.nih.gov/pubmed/16417482?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/15950877?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/16722246?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/12354619?dopt=AbstractPlus] for reviews). GlyT1 transporter isoforms expressed in glia surrounding glutamatergic synapses regulate synaptic http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=727 concentrations influencing NMDA receptor‐mediated neurotransmission [http://www.ncbi.nlm.nih.gov/pubmed/9861038?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/15555781?dopt=AbstractPlus], but also are important, in early neonatal life, for regulating glycine concentrations at inhibitory glycinergic synapses [http://www.ncbi.nlm.nih.gov/pubmed/14622582?dopt=AbstractPlus]. 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 [http://www.ncbi.nlm.nih.gov/pubmed/14622582?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/15159536?dopt=AbstractPlus]. 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 [http://www.ncbi.nlm.nih.gov/pubmed/16554468?dopt=AbstractPlus]. 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 [http://www.ncbi.nlm.nih.gov/pubmed/14622583?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/18815261?dopt=AbstractPlus]. Mice in which GlyT2 has been deleted develop a fatal hyperekplexia phenotype during the second postnatal week [http://www.ncbi.nlm.nih.gov/pubmed/14622583?dopt=AbstractPlus] and mutations in the human gene encoding GlyT2 (SLC6A5) have been identified in patients with hyperekplexia (reviewed by [http://www.ncbi.nlm.nih.gov/pubmed/18707791?dopt=AbstractPlus]). ATB0+ (SLC6A14) 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 [http://www.ncbi.nlm.nih.gov/pubmed/12719981?dopt=AbstractPlus]. ATB0+ is expressed in various peripheral tissues [http://www.ncbi.nlm.nih.gov/pubmed/12719981?dopt=AbstractPlus]. 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 http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3314.
Comments
http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4713 is a selective transportable inhibitor of GlyT1 and also a weak agonist at the http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=727 binding site of the NMDA receptor [http://www.ncbi.nlm.nih.gov/pubmed/19433577?dopt=AbstractPlus], but has no effect on GlyT2. This difference has been attributed to a single glycine residue in TM6 (serine residue in GlyT2) [http://www.ncbi.nlm.nih.gov/pubmed/17383967?dopt=AbstractPlus]. Inhibition of GLYT1 by the sarcosine derivatives http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4620, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4601 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4600 is non‐competitive [http://www.ncbi.nlm.nih.gov/pubmed/12941372?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/18815213?dopt=AbstractPlus]. IC50 values for http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4600 reported in the literature vary, most likely due to differences in assay conditions [http://www.ncbi.nlm.nih.gov/pubmed/11454468?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/12941372?dopt=AbstractPlus]. The tricyclic antidepressant http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=201 weakly inhibits GlyT2 (IC50 92 μM) with approximately 10‐fold selectivity over GlyT1 [http://www.ncbi.nlm.nih.gov/pubmed/10694221?dopt=AbstractPlus]. The endogenous lipids http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2391 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2364 exert opposing effects upon GlyT1a, inhibiting (IC50 2 μM) and potentiating (EC50 13 μM) transport currents, respectively [http://www.ncbi.nlm.nih.gov/pubmed/12558979?dopt=AbstractPlus]. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5493, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5494 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5495 have been described as endogenous non‐competitive inhibitors of GlyT2a, but not GlyT1b [http://www.ncbi.nlm.nih.gov/pubmed/19875446?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/20860669?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/16899062?dopt=AbstractPlus]. Protons [http://www.ncbi.nlm.nih.gov/pubmed/10860934?dopt=AbstractPlus] and Zn2+ [http://www.ncbi.nlm.nih.gov/pubmed/15031290?dopt=AbstractPlus] act as non‐competitive inhibitors of GlyT1b, with IC50 values of 100 nM and 10 μM respectively, but neither ion affects GlyT2 (reviewed by [http://www.ncbi.nlm.nih.gov/pubmed/15324920?dopt=AbstractPlus]). Glycine transport by GLYT1 is inhibited by http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5212, whereas GLYT2 transport is stimulated (both in the presence of Na+) [http://www.ncbi.nlm.nih.gov/pubmed/21574997?dopt=AbstractPlus].
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=179
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), SLC6A18, SLC6A20). Others may function as transporters for neurotransmitters or their precursors (i.e. B0AT2, SLC6A17) [http://www.ncbi.nlm.nih.gov/pubmed/18400692?dopt=AbstractPlus]. B0AT1 has been proposed as a drug target to treat phenylketonuria [http://www.ncbi.nlm.nih.gov/pubmed/30046012?dopt=AbstractPlus].
Further reading on SLC6 neurotransmitter transporter family
Bermingham DP et al. (2016) Kinase‐dependent Regulation of Monoamine Neurotransmitter Transporters. Pharmacol. Rev. 68: 888‐953 [https://www.ncbi.nlm.nih.gov/pubmed/27591044?dopt=AbstractPlus]
Bröer S et al. (2012) The solute carrier 6 family of transporters. Br. J. Pharmacol. 167: 256‐78 [https://www.ncbi.nlm.nih.gov/pubmed/22519513?dopt=AbstractPlus]
Joncquel‐Chevalier Curt M et al. (2015) Creatine biosynthesis and transport in health and disease. Biochimie 119: 146‐65 [https://www.ncbi.nlm.nih.gov/pubmed/26542286?dopt=AbstractPlus]
Lohr KM et al. (2017) Membrane transporters as mediators of synaptic dopamine dynamics: implications for disease. Eur. J. Neurosci. 45: 20‐33 [https://www.ncbi.nlm.nih.gov/pubmed/27520881?dopt=AbstractPlus]
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=180
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 (http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=138#159_overview) and sarcoplasmic/endoplasmic reticulum Ca2+‐ATPase (http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=138), as well as the sodium/potassium/calcium exchangers (NKCX, http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=202), 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.
Comments
Although subtype‐selective inhibitors of NCX function are not widely available, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4597 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4593 act as non‐selective NCX inhibitors, while http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4617, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4232, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4666, and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6481 [http://www.ncbi.nlm.nih.gov/pubmed/23647096?dopt=AbstractPlus] act to inhibit NCX function with varying degrees of selectivity. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=8438 is a selective NCX3 inhibitor [http://www.ncbi.nlm.nih.gov/pubmed/25942323?dopt=AbstractPlus] and and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=9484 inhibits NCX3 preferentially over other isoforms [http://www.ncbi.nlm.nih.gov/pubmed/16973719?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/27480939?dopt=AbstractPlus].
Further reading on SLC8 family of sodium/calcium exchangers
Giladi M et al. (2016) Structure‐Functional Basis of Ion Transport in Sodium‐Calcium Exchanger (NCX) Proteins. Int J Mol Sci 17: [https://www.ncbi.nlm.nih.gov/pubmed/27879668?dopt=AbstractPlus]
Khananshvili D. (2013) The SLC8 gene family of sodium‐calcium exchangers (NCX) ‐ structure, function, and regulation in health and disease. Mol. Aspects Med. 34: 220‐35 [https://www.ncbi.nlm.nih.gov/pubmed/23506867?dopt=AbstractPlus]
Sekler I. (2015) Standing of giants shoulders the story of the mitochondrial Na(+)Ca(2+) exchanger. Biochem. Biophys. Res. Commun. 460: 50‐2 [https://www.ncbi.nlm.nih.gov/pubmed/25998733?dopt=AbstractPlus]
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=181
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 intracellularmembranes [http://www.ncbi.nlm.nih.gov/pubmed/11641397?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/15522866?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/11279194?dopt=AbstractPlus]. 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 [http://www.ncbi.nlm.nih.gov/pubmed/14634667?dopt=AbstractPlus] and osteoclasts [http://www.ncbi.nlm.nih.gov/pubmed/18269914?dopt=AbstractPlus]; gene disruption results in infertile male mice [http://www.ncbi.nlm.nih.gov/pubmed/14634667?dopt=AbstractPlus].
Information on members of this family may be found in the http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=181.
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 http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4595 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4186 exhibit a rank order of affinity of inhibition of NHE1 > NHE2 > NHE3 [http://www.ncbi.nlm.nih.gov/pubmed/8246907?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/8415663?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/7685025?dopt=AbstractPlus].
Further reading on SLC9 family of sodium/hydrogen exchangers
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 [https://www.ncbi.nlm.nih.gov/pubmed/23506868?dopt=AbstractPlus]
Kato A et al. (2011) Regulation of electroneutral NaCl absorption by the small intestine. Annu. Rev. Physiol. 73: 261‐81 [https://www.ncbi.nlm.nih.gov/pubmed/21054167?dopt=AbstractPlus]
Ohgaki R et al. (2011) Organellar Na+/H+ exchangers: novel players in organelle pH regulation and their emerging functions. Biochemistry 50: 443‐50 [https://www.ncbi.nlm.nih.gov/pubmed/21171650?dopt=AbstractPlus]
Parker MD et al. (2015) Na+‐H+ exchanger‐1 (NHE1) regulation in kidney proximal tubule. Cell. Mol. Life Sci. 72: 2061‐74 [https://www.ncbi.nlm.nih.gov/pubmed/25680790?dopt=AbstractPlus]
Ruffin VA et al. (2014) Intracellular pH regulation by acid‐base transporters in mammalian neurons. Front Physiol 5: 43 [https://www.ncbi.nlm.nih.gov/pubmed/24592239?dopt=AbstractPlus]
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=182
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 andMRP2/ABCC2) and the organic solute transporter obligate heterodimer OSTa:OSTß (SLC51), to maintain the enterohepatic circulation of bile acids [http://www.ncbi.nlm.nih.gov/pubmed/19498215?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/20103563?dopt=AbstractPlus]. SLC10A6 (SOAT) functions as a sodium‐dependent transporter of sulphated solutes including sulfphated steroids and bile acids [http://www.ncbi.nlm.nih.gov/pubmed/17491011?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/15020217?dopt=AbstractPlus]. 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 [http://www.ncbi.nlm.nih.gov/pubmed/17632081?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/15020217?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/17628207?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/19682536?dopt=AbstractPlus]. Members of the SLC10 family are predicted to have seven transmembrane domains with an extracellular N‐terminus and cytoplasmic C‐terminus [http://www.ncbi.nlm.nih.gov/pubmed/16411770?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/10471288?dopt=AbstractPlus].
Comments
Heterologously expressed SLC10A4 [http://www.ncbi.nlm.nih.gov/pubmed/18355966?dopt=AbstractPlus] or SLC10A7 [http://www.ncbi.nlm.nih.gov/pubmed/17628207?dopt=AbstractPlus] failed to exhibit significant transport of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4547, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4290, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4528 or http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4551. SLC10A4 has recently been suggested to associate with neuronal vesicles [http://www.ncbi.nlm.nih.gov/pubmed/21742018?dopt=AbstractPlus].
Further reading on SLC10 family of sodium‐bile acid co‐transporters
Anwer MS et al. (2014) Sodium‐dependent bile salt transporters of the SLC10A transporter family: more than solute transporters. Pflugers Arch. 466: 77‐89 [https://www.ncbi.nlm.nih.gov/pubmed/24196564?dopt=AbstractPlus]
Claro da Silva T et al. (2013) The solute carrier family 10 (SLC10): beyond bile acid transport. Mol. Aspects Med. 34: 252‐69 [https://www.ncbi.nlm.nih.gov/pubmed/23506869?dopt=AbstractPlus]
Dawson PA. (2017) Roles of Ileal ASBT and OSTa‐OSTß in Regulating Bile Acid Signaling. Dig Dis 35: 261‐266 [https://www.ncbi.nlm.nih.gov/pubmed/28249269?dopt=AbstractPlus]
Zwicker BL et al. (2013) Transport and biological activities of bile acids. Int. J. Biochem. Cell Biol. 45: 1389‐98 [https://www.ncbi.nlm.nih.gov/pubmed/23603607?dopt=AbstractPlus]
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=183
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. SLC11A2/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 (http://omim.org/entry/607948). Loss‐of‐function mutations in DMT1 are associated with microcytic anemia (http://omim.org/entry/206100).
Further reading on SLC11 family of proton‐coupled metal ion transporters
Codazzi F et al. (2015) Iron entry in neurons and astrocytes: a link with synaptic activity. Front Mol Neurosci 8: 18 [https://www.ncbi.nlm.nih.gov/pubmed/26089776?dopt=AbstractPlus]
Montalbetti N et al. (2013) Mammalian iron transporters: families SLC11 and SLC40. Mol. Aspects Med. 34: 270‐87 [https://www.ncbi.nlm.nih.gov/pubmed/23506870?dopt=AbstractPlus]
Wessling‐Resnick M. (2015) Nramp1 and Other Transporters Involved in Metal Withholding during Infection. J. Biol. Chem. 290: 18984‐90 [https://www.ncbi.nlm.nih.gov/pubmed/26055722?dopt=AbstractPlus]
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 [https://www.ncbi.nlm.nih.gov/pubmed/22115751?dopt=AbstractPlus]
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=184
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 kidneyspecific (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.
Comments
http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4589 is able to differentiate KCC isoforms from NKCC and NCC transporters, but also inhibits CFTR [http://www.ncbi.nlm.nih.gov/pubmed/11527541?dopt=AbstractPlus].
Further reading on SLC12 family of cation‐coupled chloride transporters
Arroyo JP et al. (2013) The SLC12 family of electroneutral cation‐coupled chloride cotransporters. Mol. Aspects Med. 34: 288‐98 [https://www.ncbi.nlm.nih.gov/pubmed/23506871?dopt=AbstractPlus]
Bachmann S et al. (2017) Regulation of renal Na‐(K)‐Cl cotransporters by vasopressin. Pflugers Arch. 469: 889‐897 [https://www.ncbi.nlm.nih.gov/pubmed/28577072?dopt=AbstractPlus]
Bazúa‐Valenti S et al. (2016) Physiological role of SLC12 family members in the kidney. Am. J. Physiol. Renal Physiol. 311: F131‐44 [https://www.ncbi.nlm.nih.gov/pubmed/27097893?dopt=AbstractPlus]
Huang X et al. (2016) Everything we always wanted to know about furosemide but were afraid to ask. Am. J. Physiol. Renal Physiol. 310: F958‐71 [https://www.ncbi.nlm.nih.gov/pubmed/26911852?dopt=AbstractPlus]
Kahle KT et al. (2015) K‐Cl cotransporters, cell volume homeostasis, and neurological disease. Trends Mol Med 21: 513‐23 [https://www.ncbi.nlm.nih.gov/pubmed/26142773?dopt=AbstractPlus]
Martín‐Aragón Baudel MA et al. (2017) Chloride co‐transporters as possible therapeutic targets for stroke. J. Neurochem. 140: 195‐209 [https://www.ncbi.nlm.nih.gov/pubmed/27861901?dopt=AbstractPlus]
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=185
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.
Further reading on SLC13 family of sodium‐dependent sulphate/carboxylate transporters
Bergeron MJ et al. (2013) SLC13 family of Na+‐coupled di‐ and tri‐carboxylate/sulfate transporters. Mol. Aspects Med. 34: 299‐312 [https://www.ncbi.nlm.nih.gov/pubmed/23506872?dopt=AbstractPlus]
Markovich D. (2014) Na+‐sulfate cotransporter SLC13A1. Pflugers Arch. 466: 131‐7 [https://www.ncbi.nlm.nih.gov/pubmed/24193406?dopt=AbstractPlus]
Pajor AM. (2014) Sodium‐coupled dicarboxylate and citrate transporters from the SLC13 family. Pflugers Arch. 466: 119‐30 [https://www.ncbi.nlm.nih.gov/pubmed/24114175?dopt=AbstractPlus]
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=186
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 http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4539 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 [http://www.ncbi.nlm.nih.gov/pubmed/21449978?dopt=AbstractPlus]. 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 TMdomains, equivalent to a combination of theUT‐A2 and UT‐A3 splice variants.
Further reading on SLC14 family of facilitative urea transporters
Esteva‐Font C et al. (2015) Urea transporter proteins as targets for small‐molecule diuretics. Nat Rev Nephrol 11: 113‐23 [https://www.ncbi.nlm.nih.gov/pubmed/25488859?dopt=AbstractPlus]
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 [https://www.ncbi.nlm.nih.gov/pubmed/26085670?dopt=AbstractPlus]
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 [https://www.ncbi.nlm.nih.gov/pubmed/23364530?dopt=AbstractPlus]
Shayakul C et al. (2013) The urea transporter family (SLC14): physiological, pathological and structural aspects. Mol. Aspects Med. 34: 313‐22 [https://www.ncbi.nlm.nih.gov/pubmed/23506873?dopt=AbstractPlus]
Stewart G. (2011) The emerging physiological roles of the SLC14A family of urea transporters. Br. J. Pharmacol. 164: 1780‐92 [https://www.ncbi.nlm.nih.gov/pubmed/21449978?dopt=AbstractPlus]
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=187
Overview
The Solute Carrier 15 (SLC15) family of peptide transporters, alias H+‐coupled oligopeptide cotransporter family, is a group of membrane transporters known for their key role in the cellular uptake of di‐ and tripeptides (di/tripeptides). Of its members, SLC15A1 (PEPT1) chiefly mediates intestinal absorption of luminal di/tripeptides from overall dietary protein digestion, SLC15A2 (PEPT2) mainly allows renal tubular reuptake of di/tripeptides from ultrafiltration and brain‐to‐blood efflux of di/tripeptides in the choroid plexus, SLC15A3 (PHT2) and SLC15A4 (PHT1) interact with both di/tripeptides and histidine, e.g. in certain immune cells, and SLC15A5 has unknown physiological function. In addition, the SLC15 family of peptide transporters variably interacts with a very large number of peptidomimetics and peptide‐like drugs. It is conceivable, based on the currently acknowledged structural and functional differences, to divide the SLC15 family of peptide transporters into two subfamilies.
Comments
The members of the SLC15 family of peptide transporters are particularly promiscuous in the transport of di/tripeptides, and D‐amino acid containing peptides are also transported. While SLC15A3 and SLC15A4 transport histidine, none of them transport tetrapeptides. In addition, many molecules, among which beta‐lactam antibiotics, angiotensinconverting enzyme inhibitors and sartans, variably interact with the SLC15 family transporters. Known substrates include http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4831, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4824, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4784, L‐Dopa prodrugs, gemcitabine prodrugs, floxuridine prodrugs, Maillard reaction products, JBP485, zanamivir, oseltamivir prodrugs, doxorubicin prodrugs, polymyxins, and didanosine prodrugs. Frequently used pharmaceutical excipients such as Tween®20, Tween®80, Solutol ®HS 15 and Cremophor EL®strongly inhibit cellular uptake of Gly‐Sar by SLC15A1 and/or SLC15A2 [http://www.ncbi.nlm.nih.gov/pubmed/27903454?dopt=AbstractPlus]. There is evidence to suggest the existence of a fifth member of this transporter family, https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:33455 (http://www.uniprot.org/uniprot/A6NIM6; http://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000188991;r=12:16188485‐16277685;t=ENST00000344941), but to date there is no established biological function or reported pharmacology for this protein [http://www.ncbi.nlm.nih.gov/pubmed/21044875?dopt=AbstractPlus].
Further reading on SLC15 family of peptide transporters
Anderson CM et al. (2010) Hijacking solute carriers for proton‐coupled drug transport. Physiology (Bethesda) 25: 364‐77 [https://www.ncbi.nlm.nih.gov/pubmed/21186281?dopt=AbstractPlus]
Brandsch M. (2013) Drug transport via the intestinal peptide transporter PepT1. Curr Opin Pharmacol 13: 881‐7 [https://www.ncbi.nlm.nih.gov/pubmed/24007794?dopt=AbstractPlus]
Brandsch M. (2009) Transport of drugs by proton‐coupled peptide transporters: pearls and pitfalls. Expert Opin Drug Metab Toxicol 5: 887‐905 [https://www.ncbi.nlm.nih.gov/pubmed/19519280?dopt=AbstractPlus]
Fredriksson R et al. (2008) The solute carrier (SLC) complement of the human genome: phylogenetic classification reveals four major families. FEBS Lett. 582: 3811‐6 [https://www.ncbi.nlm.nih.gov/pubmed/18948099?dopt=AbstractPlus]
Newstead S. (2015) Molecular insights into proton coupled peptide transport in the PTR family of oligopeptide transporters. Biochim. Biophys. Acta 1850: 488‐499 [https://www.ncbi.nlm.nih.gov/pubmed/24859687?dopt=AbstractPlus]
Newstead S. (2017) Recent advances in understanding proton coupled peptide transport via the POT family. Curr. Opin. Struct. Biol. 45: 17‐24 [https://www.ncbi.nlm.nih.gov/pubmed/27865112?dopt=AbstractPlus]
Newstead S. (2011) Towards a structural understanding of drug and peptide transport within the proton‐dependent oligopeptide transporter (POT) family. Biochem. Soc. Trans. 39: 1353‐8 [https://www.ncbi.nlm.nih.gov/pubmed/21936814?dopt=AbstractPlus]
Smith DE et al. (2013) Proton‐coupled oligopeptide transporter family SLC15: physiological, pharmacological and pathological implications. Mol. Aspects Med. 34: 323‐36 [https://www.ncbi.nlm.nih.gov/pubmed/23506874?dopt=AbstractPlus]
Thwaites DT et al. (2007) H+‐coupled nutrient, micronutrient and drug transporters in the mammalian small intestine. Exp. Physiol. 92: 603‐19 [https://www.ncbi.nlm.nih.gov/pubmed/17468205?dopt=AbstractPlus]
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=188
Overview
Members of the SLC16 family may be divided into subfamilies on the basis of substrate selectivities, particularly lactate (e.g. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2932), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4809 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‐coupledmonocarboxylate transporters (monocarboxylate transporters 1, 4, 2 and 3) allowtransport of the products of cellularmetabolism, principally lactate (e.g. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2932) and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4809.
Comments
MCT1 and MCT2, but not MCT3 and MCT4, are inhibited by CHC, which also inhibits members of the mitochondrial transporter family, http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=147.
MCT5‐MCT7, MCT9 and MCT11‐14 are regarded as orphan transporters.
Further reading on SLC16 family of monocarboxylate transporters
Bernal J et al. (2015) Thyroid hormone transporters‐functions and clinical implications. Nat Rev Endocrinol 11: 406‐417 https://www.ncbi.nlm.nih.gov/pubmed/25942657?dopt=AbstractPlus
Halestrap AP. (2013) The SLC16 gene family ‐ structure, role and regulation in health and disease. Mol. Aspects Med. 34: 337‐49 https://www.ncbi.nlm.nih.gov/pubmed/23506875?dopt=AbstractPlus
Jones RS et al. (2016) Monocarboxylate Transporters: Therapeutic Targets and Prognostic Factors in Disease. Clin. Pharmacol. Ther. 100: 454‐463 https://www.ncbi.nlm.nih.gov/pubmed/27351344?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=145
Overview
The SLC17 family are sometimes referred to as Type I sodium‐phosphate co‐transporters, alongside Type II (http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=221) and Type III (http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=195) transporters. Within the SLC17 family, however, further subgroups of organic anion transporters may be defined, allowing the accumulation of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4644 in the endoplasmic reticulum and glutamate (e.g. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1369) or nucleotides in synaptic and secretory vesicles. Topology modelling suggests 12 TM domains.
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=189
Overview
Type I sodium‐phosphate co‐transporters are expressed in the kidney and intestine.
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=190
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 [446], driven by proton gradients. In lysosomes, degradation of glycoproteins generates amino acids and sugar residues, which are metabolized further following export from the lysosome.
Comments
Loss‐of‐function mutations in sialin are associated with Salla disease (http://omim.org/entry/604369), an autosomal recessive neurodegenerative disorder associated with sialic acid storage disease [http://www.ncbi.nlm.nih.gov/pubmed/10581036?dopt=AbstractPlus].
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=191
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 [http://www.ncbi.nlm.nih.gov/pubmed/10938000?dopt=AbstractPlus].
Comments
Endogenous ketoacids produced during fasting have been proposed to regulate VGLUT function through blocking chloride ion‐mediated allosteric enhancement of transporter function [http://www.ncbi.nlm.nih.gov/pubmed/20920794?dopt=AbstractPlus].
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=192
Overview
The vesicular nucleotide transporter is the most recent member of the SLC17 family to have an assigned function. Uptake of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1713 was independent of pH, but dependent on chloride ions and membrane potential [http://www.ncbi.nlm.nih.gov/pubmed/18375752?dopt=AbstractPlus].
| Nomenclature | http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1010 |
| Systematic nomenclature | SLC17A9 |
| Common abbreviation | VNUT |
| HGNC, UniProt | https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:16192, http://www.uniprot.org/uniprot/Q9BYT1 |
| Endogenous substrates | http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2410 [http://www.ncbi.nlm.nih.gov/pubmed/18375752?dopt=AbstractPlus], http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1742 [http://www.ncbi.nlm.nih.gov/pubmed/18375752?dopt=AbstractPlus], http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1713 [http://www.ncbi.nlm.nih.gov/pubmed/18375752?dopt=AbstractPlus] |
| Stoichiometry | Unknown |
| Selective inhibitors | http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=9605 (pIC50 7.8) [346] |
Comments
VGLUTs and VNUT can be inhibited by http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4177 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4579.
Further reading on SLC17 phosphate and organic anion transporter family
Moriyama Y et al. (2017) Vesicular nucleotide transporter (VNUT): appearance of an actress on the stage of purinergic signaling. Purinergic Signal. 13: 387‐404 https://www.ncbi.nlm.nih.gov/pubmed/28616712?dopt=AbstractPlus
Omote H et al. (2016) Structure, Function, and Drug Interactions of Neurotransmitter Transporters in the Postgenomic Era. Annu. Rev. Pharmacol. Toxicol. 56: 385‐402 https://www.ncbi.nlm.nih.gov/pubmed/26514205?dopt=AbstractPlus
Reimer RJ. (2013) SLC17: a functionally diverse family of organic anion transporters. Mol. Aspects Med. 34: 350‐9 https://www.ncbi.nlm.nih.gov/pubmed/23506876?dopt=AbstractPlus
Takamori S. (2016) Vesicular glutamate transporters as anion channels? Pflugers Arch. 468: 513‐8 https://www.ncbi.nlm.nih.gov/pubmed/26577586?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=193
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 http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=137#V‐typeATPase that acidifies secretory vesicles (reviewed by [http://www.ncbi.nlm.nih.gov/pubmed/12827358?dopt=AbstractPlus]). The vesicular acetylcholine transporter (VAChT; [http://www.ncbi.nlm.nih.gov/pubmed/8071310?dopt=AbstractPlus]) localizes to cholinergic neurons, but non‐neuronal expression has also been claimed [http://www.ncbi.nlm.nih.gov/pubmed/21482687?dopt=AbstractPlus]. Vesicular monoamine transporter 1 (VMAT1, [http://www.ncbi.nlm.nih.gov/pubmed/8245983?dopt=AbstractPlus]) is mainly expressed in peripheral neuroendocrine cells, but most likely not in the CNS, whereas VMAT2 [http://www.ncbi.nlm.nih.gov/pubmed/8643547?dopt=AbstractPlus] distributes between both central and peripheral sympathetic monoaminergic neurones [http://www.ncbi.nlm.nih.gov/pubmed/21272013?dopt=AbstractPlus]. The vescular polyamine transporter (VPAT) is highly expressed in the lungs and placenta, with moderate expression in brain and testis, and with low expression in heart and skeletal muscle [http://www.ncbi.nlm.nih.gov/pubmed/25355561?dopt=AbstractPlus]. VPAT mediates vesicular accumulation of polyamines in mast cells [http://www.ncbi.nlm.nih.gov/pubmed/28082679?dopt=AbstractPlus].
Comments
pKi values for endogenous and synthetic substrate inhibitors of human VMAT1 and VMAT2 are for inhibition of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3248 uptake in transfected and permeabilised CV‐1 cells as detailed by [http://www.ncbi.nlm.nih.gov/pubmed/8643547?dopt=AbstractPlus]. In addition to the monoamines listed in the table, the trace amines http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2150 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2144 are probable substrates for VMAT2 [http://www.ncbi.nlm.nih.gov/pubmed/21272013?dopt=AbstractPlus]. Probes listed in the table are those currently employed; additional agents have been synthesized (e.g. [http://www.ncbi.nlm.nih.gov/pubmed/19632829?dopt=AbstractPlus]).
Further reading on SLC18 family of vesicular amine transporters
German CL et al. (2015) Regulation of the Dopamine and Vesicular Monoamine Transporters: Pharmacological Targets and Implications for Disease. Pharmacol. Rev. 67: 1005‐24 https://www.ncbi.nlm.nih.gov/pubmed/26408528?dopt=AbstractPlus
Lohr KM et al. (2017) Membrane transporters as mediators of synaptic dopamine dynamics: implications for disease. Eur. J. Neurosci. 45: 20‐33 https://www.ncbi.nlm.nih.gov/pubmed/27520881?dopt=AbstractPlus
Omote H et al. (2016) Structure, Function, and Drug Interactions of Neurotransmitter Transporters in the Postgenomic Era. Annu. Rev. Pharmacol. Toxicol. 56: 385‐402 https://www.ncbi.nlm.nih.gov/pubmed/26514205?dopt=AbstractPlus
Sitte HH et al. (2015) Amphetamines, new psychoactive drugs and the monoamine transporter cycle. Trends Pharmacol. Sci. 36: 41‐50 https://www.ncbi.nlm.nih.gov/pubmed/25542076?dopt=AbstractPlus
Wimalasena K. (2011) Vesicular monoamine transporters: structure‐function, pharmacology, and medicinal chemistry. Med Res Rev 31: 483‐519 https://www.ncbi.nlm.nih.gov/pubmed/20135628?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=194
Overview
The B vitamins http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4563 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4629 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.
Comments
Loss‐of‐function mutations in ThTr1 underlie thiamine‐responsive megaloblastic anemia syndrome [http://www.ncbi.nlm.nih.gov/pubmed/10391223?dopt=AbstractPlus].
Further reading on SLC19 family of vitamin transporters
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 https://www.ncbi.nlm.nih.gov/pubmed/24396145?dopt=AbstractPlus
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 https://www.ncbi.nlm.nih.gov/pubmed/23506878?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=195
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 (http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=145) and Type II (http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=221). PiTs are cell‐surface transporters, composed of ten TM domains with extracellular C‐ and N‐termini. PiT1 is a focus for dietary phosphate and http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=90 regulation of parathyroid hormone secretion from the parathyroid gland. PiT2 appears to be involved in intestinal absorption of dietary phosphate.
| Nomenclature | http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1017 | http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1018 |
| Systematic nomenclature | SLC20A1 | SLC20A2 |
| Common abbreviation | PiT1 | PiT2 |
| HGNC, UniProt | https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:10946, http://www.uniprot.org/uniprot/Q8WUM9 | https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:10947, http://www.uniprot.org/uniprot/Q08357 |
| Substrates | AsO4 3‐ [http://www.ncbi.nlm.nih.gov/pubmed/17494632?dopt=AbstractPlus], phosphate [http://www.ncbi.nlm.nih.gov/pubmed/17494632?dopt=AbstractPlus] | phosphate [http://www.ncbi.nlm.nih.gov/pubmed/17494632?dopt=AbstractPlus] |
| Stoichiometry | >1 Na+ : 1 HPO4 2‐ (in) | >1 Na+ : 1 HPO4 2‐ (in) |
Further reading on SLC20 family of sodium‐dependent phosphate transporters
Biber J et al. (2013) Phosphate transporters and their function. Annu. Rev. Physiol. 75: 535‐50 https://www.ncbi.nlm.nih.gov/pubmed/23398154?dopt=AbstractPlus
Forster IC et al. (2013) Phosphate transporters of the SLC20 and SLC34 families. Mol. Aspects Med. 34: 386‐95 https://www.ncbi.nlm.nih.gov/pubmed/23506879?dopt=AbstractPlus
Shobeiri N et al. (2014) Phosphate: an old bone molecule but new cardiovascular risk factor. Br J Clin Pharmacol 77: 39‐54 https://www.ncbi.nlm.nih.gov/pubmed/23506202?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=146
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.
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=196
Overview
Organic cation transporters (OCT) are electrogenic, Na+‐independent and reversible.
Comments
http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2869 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2510 are able to inhibit all three organic cation transporters.
Further reading on Organic cation transporters (OCT)
Koepsell H. (2013) The SLC22 family with transporters of organic cations, anions and zwitterions. Mol. Aspects Med. 34: 413‐35 https://www.ncbi.nlm.nih.gov/pubmed/23506881?dopt=AbstractPlus
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 https://www.ncbi.nlm.nih.gov/pubmed/23984399?dopt=AbstractPlus
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 https://www.ncbi.nlm.nih.gov/pubmed/24745985?dopt=AbstractPlus
Yin J et al. (2016) Renal drug transporters and their significance in drug‐drug interactions. Acta Pharm Sin B 6: 363‐373 https://www.ncbi.nlm.nih.gov/pubmed/27709005?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=197
Overview
Organic zwitterions/cation transporters (OCTN) function as organic cation uniporters, organic cation/proton exchangers or sodium/http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4780 co‐transporters.
Comments
Mutations in the SLC22A5 gene lead to primary carnitine deficiency [http://www.ncbi.nlm.nih.gov/pubmed/26828774?dopt=AbstractPlus].
Further reading on Organic zwitterions/cation transporters (OCTN)
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 https://www.ncbi.nlm.nih.gov/pubmed/23771822?dopt=AbstractPlus
Tamai I. (2013) Pharmacological and pathophysiological roles of carnitine/organic cation transporters (OCTNs: SLC22A4, SLC22A5 and Slc22a21). Biopharm Drug Dispos 34: 29‐44 https://www.ncbi.nlm.nih.gov/pubmed/22952014?dopt=AbstractPlus
Yin J et al. (2016) Renal drug transporters and their significance in drug‐drug interactions. Acta Pharm Sin B 6: 363‐373 https://www.ncbi.nlm.nih.gov/pubmed/27709005?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=198
Overview
Organic anion transporters (OATs) are non‐selective transporters prominent in the kidney, placenta and blood‐brain barrier.
Further reading on Organic anion transporters (OATs)
Burckhardt G et al. (2011) In vitro and in vivo evidence of the importance of organic anion transporters (OATs) in drug therapy. Handb Exp Pharmacol 29‐104 https://www.ncbi.nlm.nih.gov/pubmed/21103968?dopt=AbstractPlus
Koepsell H. (2013) The SLC22 family with transporters of organic cations, anions and zwitterions. Mol. Aspects Med. 34: 413‐35 https://www.ncbi.nlm.nih.gov/pubmed/23506881?dopt=AbstractPlus
Shen H et al. (2017) Organic Anion Transporter 2: An Enigmatic Human Solute Carrier. Drug Metab. Dispos. 45: 228‐236 https://www.ncbi.nlm.nih.gov/pubmed/27872146?dopt=AbstractPlus
Yin J et al. (2016) Renal drug transporters and their significance in drug‐drug interactions. Acta Pharm Sin B 6: 363‐373 https://www.ncbi.nlm.nih.gov/pubmed/27709005?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=199
Overview
URAT1, a member of the OAT (organic anion transporter) family, is an anion‐exchanging uptake transporter localized to the apical (brush border) membrane of renal proximal tubular cells. It is an anion exchanger that specifically reabsorbs uric acid from the proximal tubule in exchange for monovalent anions such as lactate, nicotinoate, acetoacetate, and hydroxybutyrate [http://www.ncbi.nlm.nih.gov/pubmed/12024214?dopt=AbstractPlus].
Further reading on Urate transporter
Nigam SK et al. (2018) The systems biology of uric acid transporters: the role of remote sensing and signaling. Curr. Opin. Nephrol. Hypertens. 27: 305‐313 https://www.ncbi.nlm.nih.gov/pubmed/29847376?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=859
Overview
This family of transporters has previously been classified as part of the atypical major facilitator superfamily (MSF) protein superfamily [http://www.ncbi.nlm.nih.gov/pubmed/9529885?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/28878041?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/27939446?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/22458847?dopt=AbstractPlus]. The atypical SLCs share sequence similarities and phylogenetic ancestry with other SLCs, and they have historically been classified in to subfamilies (also referred to as atypical MFS transporter families (AMTF1‐15)) based on phylogenetic, sequence and structural analyses [http://www.ncbi.nlm.nih.gov/pubmed/28878041?dopt=AbstractPlus].
| Nomenclature | http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2634 |
| Systematic nomenclature | SLC22B1 |
| HGNC, UniProt | https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:20566, http://www.uniprot.org/uniprot/Q7L0J3 |
| Substrates | Galactose [http://www.ncbi.nlm.nih.gov/pubmed/25326386?dopt=AbstractPlus] |
| Inhibitors | http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=9041 (pIC50 7) [http://www.ncbi.nlm.nih.gov/pubmed/14736235?dopt=AbstractPlus] – Rat, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6826 (pK i 5.8) [http://www.ncbi.nlm.nih.gov/pubmed/8605950?dopt=AbstractPlus] – Rat |
Comments
There are three human synaptic vesicle glycoprotein 2 family members, SV2A, SV2B and SV2C. They have transmembrane transporter activity and can be classified in to the SLC superfamily of solute carriers in subfamily SLC22, as SCL22B1, B2 and B3 respectively. SV2A (SCL22B1) has been identified as the brain binding‐site for the antiepileptic drugs levetiracetam [http://www.ncbi.nlm.nih.gov/pubmed/23484603?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/27752944?dopt=AbstractPlus] and brivaracetam [http://www.ncbi.nlm.nih.gov/pubmed/26663401?dopt=AbstractPlus].
Further reading on Atypical SLC22B subfamily
Löscher W et al. (2016) Synaptic Vesicle Glycoprotein 2A Ligands in the Treatment of Epilepsy and Beyond. CNS Drugs 30: 1055‐1077 https://www.ncbi.nlm.nih.gov/pubmed/27752944?dopt=AbstractPlus
Mendoza‐Torreblanca JG et al. (2013) Synaptic vesicle protein 2A: basic facts and role in synaptic function. Eur. J. Neurosci. 38: 3529‐39 https://www.ncbi.nlm.nih.gov/pubmed/24102679?dopt=AbstractPlus
Further reading on SLC22 family of organic cation and anion transporters
Burckhardt G. (2012) Drug transport by Organic Anion Transporters (OATs). Pharmacol. Ther. 136: 106‐30 https://www.ncbi.nlm.nih.gov/pubmed/22841915?dopt=AbstractPlus
Hillgren KM et al. (2013) Emerging transporters of clinical importance: an update from the International Transporter Consortium. Clin. Pharmacol. Ther. 94: 52‐63 https://www.ncbi.nlm.nih.gov/pubmed/23588305?dopt=AbstractPlus
International Transporter Consortium et al. (2010) Membrane transporters in drug development. Nat Rev Drug Discov 9: 215‐36 https://www.ncbi.nlm.nih.gov/pubmed/20190787?dopt=AbstractPlus
Koepsell H. (2013) The SLC22 family with transporters of organic cations, anions and zwitterions. Mol. Aspects Med. 34: 413‐35 https://www.ncbi.nlm.nih.gov/pubmed/23506881?dopt=AbstractPlus
Lozano E et al. (2018) Genetic Heterogeneity of SLC22 Family of Transporters in Drug Disposition. J Pers Med 8: https://www.ncbi.nlm.nih.gov/pubmed/29659532?dopt=AbstractPlus
Nigam SK. (2018) The SLC22 Transporter Family: A Paradigm for the Impact of Drug Transporters on Metabolic Pathways, Signaling, and Disease. Annu. Rev. Pharmacol. Toxicol. 58: 663‐687 https://www.ncbi.nlm.nih.gov/pubmed/29309257?dopt=AbstractPlus
Zamek‐Gliszczynski MJ et al. (2018) Transporters in Drug Development: 2018 ITC Recommendations for Transporters of Emerging Clinical Importance. Clin. Pharmacol. Ther. 104: 890‐899 https://www.ncbi.nlm.nih.gov/pubmed/30091177?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=201
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 http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=140 (GLUT1/SLC2A1, GLUT3/SLC2A3 and GLUT4/SLC2A4). http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4285 is considered a non‐selective inhibitor of these transporters, with an affinity in the micromolar range.
Further reading on SLC23 family of ascorbic acid transporters
Bürzle M et al. (2013) The sodium‐dependent ascorbic acid transporter family SLC23. Mol. Aspects Med. 34: 436‐54 https://www.ncbi.nlm.nih.gov/pubmed/23506882?dopt=AbstractPlus
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 https://www.ncbi.nlm.nih.gov/pubmed/21418192?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=202
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 (http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=180), 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 | http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1045 | http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1050 |
| Systematic nomenclature | SLC24A1 | SLC24A6 |
| Common abbreviation | NKCX1 | NKCX6 |
| HGNC, UniProt | https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:10975, http://www.uniprot.org/uniprot/O60721 | https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:26175, http://www.uniprot.org/uniprot/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 [http://www.ncbi.nlm.nih.gov/pubmed/25998733?dopt=AbstractPlus].
Further reading on SLC24 family of sodium/potassium/calcium exchangers
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 https://www.ncbi.nlm.nih.gov/pubmed/23506883?dopt=AbstractPlus
Schnetkamp PP et al. (2014) The SLC24 family of K+‐dependent Na+‐Ca2+ exchangers: structure‐function relationships. Curr Top Membr 73: 263‐87 https://www.ncbi.nlm.nih.gov/pubmed/24745986?dopt=AbstractPlus
Sekler I. (2015) Standing of giants shoulders the story of the mitochondrial Na(+)Ca(2+) exchanger. Biochem. Biophys. Res. Commun. 460: 50‐2 https://www.ncbi.nlm.nih.gov/pubmed/25998733?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=147
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.
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=203
Overview
Mitochondrial di‐ and tri‐carboxylic acid transporters are grouped on the basis of commonality of substrates and include the citrate transporter which facilitates http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2478 export from the mitochondria to allow the generation of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5236 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3038 through the action of ATP:citrate lyase.
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=204
Overview
Mitochondrial amino acid transporters can be subdivided on the basis of their substrates. Mitochondrial ornithine transporters play a role in the http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4539 cycle by exchanging cytosolic ornithine (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=725 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4682) for mitochondrial citrulline (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=722 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4683) in equimolar amounts. Further members of the family include transporters of S‐adenosylmethionine and carnitine.
Comments
Both ornithine transporters are inhibited by the polyamine http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=710 [http://www.ncbi.nlm.nih.gov/pubmed/19429682?dopt=AbstractPlus]. Loss‐of‐function mutations in these genes are associated with hyperornithinemia‐hyperammonemia‐homocitrullinuria.
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=205
Overview
Mitochondrial phosphate transporters allow the import of inorganic phosphate for http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1713 production.
| Nomenclature | http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1061 |
| Systematic nomenclature | SLC25A3 |
| Common abbreviation | PHC |
| HGNC, UniProt | https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:10989, http://www.uniprot.org/uniprot/Q00325 |
| Stoichiometry | PO3 4‐ (in) : OH‐ (out) or PO3 4‐ : H+ (in) |
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=206
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 http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1712 for mitochondrial http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1713. Further members of the mitochondrial nucleotide transporter subfamily convey diverse substrates including CoA, although not all members have had substrates identified.
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=207
Overview
Mitochondrial uncoupling proteins allow dissipation of the mitochondrial proton gradient associated with thermogenesis and regulation of radical formation.
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=209
Overview
Many of the transporters identified below have yet to be assigned functions and are currently regarded as orphans.
Information on members of this family may be found in the http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=209.
Further reading on SLC25 family of mitochondrial transporters
Baffy G. (2017) Mitochondrial uncoupling in cancer cells: Liabilities and opportunities. Biochim. Biophys. Acta 1858: 655‐664 https://www.ncbi.nlm.nih.gov/pubmed/28088333?dopt=AbstractPlus
Bertholet AM et al. (2017) UCP1: A transporter for H+ and fatty acid anions. Biochimie 134: 28‐34 https://www.ncbi.nlm.nih.gov/pubmed/27984203?dopt=AbstractPlus
Clémençon B et al. (2013) The mitochondrial ADP/ATP carrier (SLC25 family): pathological implications of its dysfunction. Mol. Aspects Med. 34: 485‐93 https://www.ncbi.nlm.nih.gov/pubmed/23506884?dopt=AbstractPlus
Palmieri F. (2013) The mitochondrial transporter family SLC25: identification, properties and physiopathology. Mol. Aspects Med. 34: 465‐84 https://www.ncbi.nlm.nih.gov/pubmed/23266187?dopt=AbstractPlus
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 https://www.ncbi.nlm.nih.gov/pubmed/26091567?dopt=AbstractPlus
Taylor EB. (2017) Functional Properties of the Mitochondrial Carrier System. Trends Cell Biol. 27: 633‐644 https://www.ncbi.nlm.nih.gov/pubmed/28522206?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=148
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).
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=210
| Nomenclature | http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1097 | http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1098 |
| Systematic nomenclature | SLC26A1 | SLC26A2 |
| HGNC, UniProt | https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:10993, http://www.uniprot.org/uniprot/Q9H2B4 | https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:10994, http://www.uniprot.org/uniprot/P50443 |
| Substrates | SO4 2‐, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4538 | SO4 2‐ |
| Stoichiometry | SO4 2‐ (in) : anion (out) | 1 SO4 2‐ (in) : 2 Cl‐ (out) |
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=211
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=212
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=213
| Nomenclature | http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1104 |
| Systematic nomenclature | SLC26A5 |
| HGNC, UniProt | https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:9359, http://www.uniprot.org/uniprot/P58743 |
| Substrates | HCO3 ‐ [http://www.ncbi.nlm.nih.gov/pubmed/22890707?dopt=AbstractPlus], http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2339 [http://www.ncbi.nlm.nih.gov/pubmed/22890707?dopt=AbstractPlus] |
| Stoichiometry | Unknown |
| Comments | Prestin has been suggested to function as a molecular motor, rather than a transporter |
Further reading on SLC26 family of anion exchangers
Alper SL et al. (2013) The SLC26 gene family of anion transporters and channels. Mol. Aspects Med. 34: 494‐515 https://www.ncbi.nlm.nih.gov/pubmed/23506885?dopt=AbstractPlus
Kato A et al. (2011) Regulation of electroneutral NaCl absorption by the small intestine. Annu. Rev. Physiol. 73: 261‐81 https://www.ncbi.nlm.nih.gov/pubmed/21054167?dopt=AbstractPlus
Nofziger C et al. (2011) Pendrin function in airway epithelia. Cell. Physiol. Biochem. 28: 571‐8 https://www.ncbi.nlm.nih.gov/pubmed/22116372?dopt=AbstractPlus
Soleimani M. (2013) SLC26 Cl‐/HCO3‐ exchangers in the kidney: roles in health and disease. Kidney Int. 84: 657‐66 https://www.ncbi.nlm.nih.gov/pubmed/23636174?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=214
Overview
Fatty acid transporter proteins (FATPs) are a family (SLC27) of six transporters (FATP1‐6). They have at least one, and possibly six [http://www.ncbi.nlm.nih.gov/pubmed/11470793?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/7954810?dopt=AbstractPlus], 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) [http://www.ncbi.nlm.nih.gov/pubmed/9079682?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/17062637?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/17065791?dopt=AbstractPlus]. These transporters are unusual in that they appear to express intrinsic very longchain acyl‐CoA synthetase (http://www.genome.jp/kegg‐bin/search_brite?option=‐a&search_string=6.2.1.‐ , http://www.genome.jp/kegg‐bin/search_brite?option=‐a&search_string=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 [http://www.ncbi.nlm.nih.gov/pubmed/11980911?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/7954810?dopt=AbstractPlus].
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 http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3044 to form fatty acyl CoA esters. Small molecule inhibitors of FATP2 [http://www.ncbi.nlm.nih.gov/pubmed/17928635?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/19913517?dopt=AbstractPlus] and FATP4 [http://www.ncbi.nlm.nih.gov/pubmed/16644217?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/20448275?dopt=AbstractPlus], as well as bile acid inhibitors of FATP5 [http://www.ncbi.nlm.nih.gov/pubmed/20448275?dopt=AbstractPlus], 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.
http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5496 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 on SLC27 family of fatty acid transporters
Anderson CM et al. (2013) SLC27 fatty acid transport proteins. Mol. Aspects Med. 34: 516–28 https://www.ncbi.nlm.nih.gov/pubmed/23506886?dopt=AbstractPlus
Dourlen P et al. (2015) Fatty acid transport proteins in disease: New insights from invertebrate models. Prog. Lipid Res. 60: 30–40 https://www.ncbi.nlm.nih.gov/pubmed/26416577?dopt=AbstractPlus
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 https://www.ncbi.nlm.nih.gov/pubmed/20206486?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=149
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.
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=215
Overview
SLC28 family membersappear to have 13 TM segments with cytoplasmic N‐termini and extracellular C‐termini, and function as concentrative nucleoside transporters.
Further reading on SLC28 family
Johnson ZL et al. (2014) Structural basis of nucleoside and nucleoside drug selectivity by concentrative nucleoside transporters. Elife 3: e03604 https://www.ncbi.nlm.nih.gov/pubmed/25082345?dopt=AbstractPlus
Pastor‐Anglada M et al. (2008) SLC28 genes and concentrative nucleoside transporter (CNT) proteins. Xenobiotica 38: 972–94 https://www.ncbi.nlm.nih.gov/pubmed/18668436?dopt=AbstractPlus
Pastor‐Anglada M et al. (2015) Nucleoside transporter proteins as biomarkers of drug responsiveness and drug targets. Front Pharmacol 6: 13 https://www.ncbi.nlm.nih.gov/pubmed/25713533?dopt=AbstractPlus
Pastor‐Anglada M et al. (2018) Who Is Who in Adenosine Transport. Front Pharmacol 9: 627 https://www.ncbi.nlm.nih.gov/pubmed/29962948?dopt=AbstractPlus
Young JD et al. (2013) The human concentrative and equilibrative nucleoside transporter families, SLC28 and SLC29. Mol. Aspects Med. 34: 529–47 https://www.ncbi.nlm.nih.gov/pubmed/23506887?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=216
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 [http://www.ncbi.nlm.nih.gov/pubmed/15701636?dopt=AbstractPlus]. ENT1‐3 are described as broad‐spectrum equilibrative nucleoside transporters, while ENT4 is primarily a polyspecific organic cation transporter at neutral pH [http://www.ncbi.nlm.nih.gov/pubmed/21816955?dopt=AbstractPlus].
Further reading on SLC29 family
Boswell‐Casteel RC et al. (2017) Equilibrative nucleoside transporters‐A review. Nucleosides Nucleotides Nucleic Acids 36: 7–30 https://www.ncbi.nlm.nih.gov/pubmed/27759477?dopt=AbstractPlus
Pastor‐Anglada M et al. (2018) Who Is Who in Adenosine Transport. Front Pharmacol 9: 627 https://www.ncbi.nlm.nih.gov/pubmed/29962948?dopt=AbstractPlus
Wang J. (2016) The plasma membranemonoamine transporter (PMAT): Structure, function, and role in organic cation disposition. Clin. Pharmacol. Ther. 100: 489–499 https://www.ncbi.nlm.nih.gov/pubmed/27506881?dopt=AbstractPlus
Further reading on SLC28 and SLC29 families of nucleoside transporters
Boswell‐Casteel RC et al. (2017) Equilibrative nucleoside transporters‐A review. Nucleosides Nucleotides Nucleic Acids 36: 7–30 https://www.ncbi.nlm.nih.gov/pubmed/27759477?dopt=AbstractPlus
Pastor‐Anglada M et al. (2015) Nucleoside transporter proteins as biomarkers of drug responsiveness and drug targets. Front Pharmacol 6: 13 https://www.ncbi.nlm.nih.gov/pubmed/25713533?dopt=AbstractPlus
Young JD. (2016) The SLC28 (CNT) and SLC29 (ENT) nucleoside transporter families: a 30‐year collaborative odyssey. Biochem. Soc. Trans. 44: 869–76 https://www.ncbi.nlm.nih.gov/pubmed/27284054?dopt=AbstractPlus
Young JD et al. (2013) The human concentrative and equilibrative nucleoside transporter families, SLC28 and SLC29. Mol. Aspects Med. 34: 529–47 https://www.ncbi.nlm.nih.gov/pubmed/23506887?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=217
Overview
Along with the http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=228, 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 [http://www.ncbi.nlm.nih.gov/pubmed/15994300?dopt=AbstractPlus], 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 [http://www.ncbi.nlm.nih.gov/pubmed/19521526?dopt=AbstractPlus]. The mechanism for zinc transport is unknown.
Information on members of this family may be found in the http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=217.
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 on SLC30 zinc transporter family
Bouron A et al. (2014) Contribution of calcium‐conducting channels to the transport of zinc ions. Pflugers Arch. 466: 381–7 https://www.ncbi.nlm.nih.gov/pubmed/23719866?dopt=AbstractPlus
Hojyo S et al. (2016) Zinc transporters and signaling in physiology and pathogenesis. Arch. Biochem. Biophys. 611: 43–50 https://www.ncbi.nlm.nih.gov/pubmed/27394923?dopt=AbstractPlus
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 https://www.ncbi.nlm.nih.gov/pubmed/23506888?dopt=AbstractPlus
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 https://www.ncbi.nlm.nih.gov/pubmed/24710731?dopt=AbstractPlus
Kambe T et al. (2015) The Physiological, Biochemical, and Molecular Roles of Zinc Transporters in Zinc Homeostasis and Metabolism. Physiol. Rev. 95: 749–784 https://www.ncbi.nlm.nih.gov/pubmed/26084690?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=218
Overview
SLC31 family members, alongside the http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=138#Cu2+‐ATPase 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 [http://www.ncbi.nlm.nih.gov/pubmed/15494390?dopt=AbstractPlus]. 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 [http://www.ncbi.nlm.nih.gov/pubmed/11734551?dopt=AbstractPlus].
| Nomenclature | http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1131 | http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1132 |
| Systematic nomenclature | SLC31A1 | SLC31A2 |
| Common abbreviation | CTR1 | CTR2 |
| HGNC, UniProt | https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:11016, http://www.uniprot.org/uniprot/O15431 | https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:11017, http://www.uniprot.org/uniprot/O15432 |
| Substrates | http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5343 [http://www.ncbi.nlm.nih.gov/pubmed/12370430?dopt=AbstractPlus] | http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5343 [http://www.ncbi.nlm.nih.gov/pubmed/19509135?dopt=AbstractPlus] |
| Endogenous substrates | copper [http://www.ncbi.nlm.nih.gov/pubmed/11734551?dopt=AbstractPlus] | copper |
| Stoichiometry | Unknown | Unknown |
Comments
Copper accumulation through CTR1 is sensitive to silver ions, but not divalent cations [http://www.ncbi.nlm.nih.gov/pubmed/11734551?dopt=AbstractPlus].
Further reading on SLC31 family of copper transporters
Howell SB et al. (2010) Copper transporters and the cellular pharmacology of the platinumcontaining cancer drugs. Mol. Pharmacol. 77: 887–94 https://www.ncbi.nlm.nih.gov/pubmed/20159940?dopt=AbstractPlus
Kaplan JH et al. (2016) How Mammalian Cells Acquire Copper: An Essential but Potentially Toxic Metal. Biophys. J. 110: 7–13 https://www.ncbi.nlm.nih.gov/pubmed/26745404?dopt=AbstractPlus
Kim H et al. (2013) SLC31 (CTR) family of copper transporters in health and disease. Mol. Aspects Med. 34: 561–70 https://www.ncbi.nlm.nih.gov/pubmed/23506889?dopt=AbstractPlus
Monne M et al. (2014) Antiporters of the mitochondrial carrier family. Curr Top Membr 73: 289–320 https://www.ncbi.nlm.nih.gov/pubmed/24745987?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=219
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 http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1067, or http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=727, into synaptic vesicles [http://www.ncbi.nlm.nih.gov/pubmed/12750892?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/10865121?dopt=AbstractPlus], and is a member of the structurally‐defined amino acid‐polyamineorganocation/ APC clan composed of SLC32, SLC36 and SLC38 transporter families (see [http://www.ncbi.nlm.nih.gov/pubmed/23506890?dopt=AbstractPlus]). VIAAT was originally suggested to be composed of 10 TM segments with cytoplasmic N‐ and C‐termini [http://www.ncbi.nlm.nih.gov/pubmed/9349821?dopt=AbstractPlus]. 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 [http://www.ncbi.nlm.nih.gov/pubmed/19052203?dopt=AbstractPlus]. VI‐AAT acts as an antiporter for inhibitory amino acids and protons. The accumulation ofGABA and glycine within vesicles is driven by both the chemical (ΔpH) and electrical (Δψ) components of the proton electrochemical gradient (ΔμH +) established by a vacuolar H+‐ATPase [http://www.ncbi.nlm.nih.gov/pubmed/9349821?dopt=AbstractPlus]. However, one study, [http://www.ncbi.nlm.nih.gov/pubmed/19843525?dopt=AbstractPlus], presented evidence that VIAAT is instead a Cl‐/GABA co‐transporter. VIAAT co‐exists with http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=145#show_object_1007 (SLC17A7), or http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=145#show_object_1008 (SLC17A6), in the synaptic vesicles of selected nerve terminals [http://www.ncbi.nlm.nih.gov/pubmed/19627441?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/20519538?dopt=AbstractPlus]. VIAAT knock out mice die between embryonic day 18.5 and birth [http://www.ncbi.nlm.nih.gov/pubmed/16701208?dopt=AbstractPlus]. In cultures of spinal cord neurones established from earlier embryos, the corelease of of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1067 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=727 from synaptic vesicles is drastically reduced, providing direct evidence for the role of VIAAT in the sequestration of both transmitters [http://www.ncbi.nlm.nih.gov/pubmed/21190592?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/16701208?dopt=AbstractPlus].
| Nomenclature | http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1133 |
| Systematic nomenclature | SLC32A1 |
| Common abbreviation | VIAAT |
| HGNC, UniProt | https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:11018, http://www.uniprot.org/uniprot/Q9H598 |
| Endogenous substrates | β‐alanine, γ‐hydroxybutyric acid, GABA (K m 5×10‐3M) [http://www.ncbi.nlm.nih.gov/pubmed/9349821?dopt=AbstractPlus], http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=727 |
| Stoichiometry | 1 amino acid (in): 1 H+ (out) [http://www.ncbi.nlm.nih.gov/pubmed/12750892?dopt=AbstractPlus] or 1 amino acid: 2Cl‐ (in) [http://www.ncbi.nlm.nih.gov/pubmed/19843525?dopt=AbstractPlus] |
| Inhibitors | http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4821 (pIC50 2.1) [http://www.ncbi.nlm.nih.gov/pubmed/9349821?dopt=AbstractPlus] |
Further reading on SLC32 vesicular inhibitory amino acid transporter
Anne C et al. (2014) Vesicular neurotransmitter transporters: mechanistic aspects. Curr Top Membr 73: 149‐74 https://www.ncbi.nlm.nih.gov/pubmed/24745982?dopt=AbstractPlus
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 https://www.ncbi.nlm.nih.gov/pubmed/23506890?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=220
Overview
Acetylation of proteins is a post‐translational modification mediated by specific acetyltransferases, using the donor http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3038. SLC33A1/AT1 is a putative 11 TM transporter present on the endoplasmic reticulum, expressed in all tissues, but particularly abundant in the pancreas [http://www.ncbi.nlm.nih.gov/pubmed/9096318?dopt=AbstractPlus], which imports cytosolic http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3038 into these intracellular organelles.
| Nomenclature | http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1134 |
| Systematic nomenclature | SLC33A1 |
| Common abbreviation | ACATN1 |
| HGNC, UniProt | https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:95, http://www.uniprot.org/uniprot/O00400 |
| Endogenous substrates | http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3038 |
| Stoichiometry | Unknown |
| Labelled ligands | http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4541 (Binding) |
Comments
In heterologous expression studies, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3038 transport through AT1 was inhibited by http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3044, but not http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1058, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1713 or http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1782[http://www.ncbi.nlm.nih.gov/pubmed/20826464?dopt=AbstractPlus]. A loss‐of‐function mutation in ACATN1/SLC33A1 has been associated with spastic paraplegia (SPG42, [http://www.ncbi.nlm.nih.gov/pubmed/19061983?dopt=AbstractPlus]), although this observation could not be replicated in a subsequent study [http://www.ncbi.nlm.nih.gov/pubmed/20461110?dopt=AbstractPlus].
Further reading on SLC33 acetylCoA transporter
Hirabayashi Y et al. (2004) The acetyl‐CoA transporter family SLC33. Pflugers Arch. 447: 760‐2 https://www.ncbi.nlm.nih.gov/pubmed/12739170?dopt=AbstractPlus
Hirabayashi Y et al. (2013) The acetyl‐CoA transporter family SLC33. Mol. Aspects Med. 34: 586‐9 https://www.ncbi.nlm.nih.gov/pubmed/23506891?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=221
Overview
The SLC34 family are sometimes referred to as Type II sodium‐phosphate co‐transporters, alongside Type I (http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=145) and Type III (http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=195) 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 [http://www.ncbi.nlm.nih.gov/pubmed/18989094?dopt=AbstractPlus].
Comments
These transporters can be inhibited by http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5497, in contrast to type III sodium‐phosphate cotransporters, the http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=195.
Further reading on SLC34 family of sodium phosphate co‐transporters
Biber J et al. (2013) Phosphate transporters and their function. Annu. Rev. Physiol. 75: 535‐50 https://www.ncbi.nlm.nih.gov/pubmed/23398154?dopt=AbstractPlus
Forster IC et al. (2013) Phosphate transporters of the SLC20 and SLC34 families. Mol. Aspects Med. 34: 386‐95 https://www.ncbi.nlm.nih.gov/pubmed/23506879?dopt=AbstractPlus
Shobeiri N et al. (2014) Phosphate: an old bone molecule but new cardiovascular risk factor. Br J Clin Pharmacol 77: 39‐54 https://www.ncbi.nlm.nih.gov/pubmed/23506202?dopt=AbstractPlus
Wagner CA et al. (2014) The SLC34 family of sodium‐dependent phosphate transporters. Pflugers Arch. 466: 139‐53 https://www.ncbi.nlm.nih.gov/pubmed/24352629?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=222
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.
Further reading on SLC35 family of nucleotide sugar transporters
Ishida N et al. (2004) Molecular physiology and pathology of the nucleotide sugar transporter family (SLC35). Pflugers Arch. 447: 768‐75 https://www.ncbi.nlm.nih.gov/pubmed/12759756?dopt=AbstractPlus
Orellana A et al. (2016) Overview of Nucleotide Sugar Transporter Gene Family Functions Across Multiple Species. J. Mol. Biol. 428: 3150‐3165 https://www.ncbi.nlm.nih.gov/pubmed/27261257?dopt=AbstractPlus
Song Z. (2013) Roles of the nucleotide sugar transporters (SLC35 family) in health and disease. Mol. Aspects Med. 34: 590‐600 https://www.ncbi.nlm.nih.gov/pubmed/23506892?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=223
Overview
Members of the SLC36 family of proton‐coupled amino acid transporters are involved in membrane transport of amino acids and derivatives. The four transporters show variable tissue expression patterns and are expressed in various cell types at the plasma‐membrane and in intracellular organelles. PAT1 is expressed at the luminal surface of the small intestine and absorbs amino acids and derivatives [3]. In lysosomes, PAT1 functions as an effluxmechanism for amino acids produced during intralysosomal proteolysis [http://www.ncbi.nlm.nih.gov/pubmed/12761825?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/11390972?dopt=AbstractPlus]. PAT2 is expressed at the apical membrane of the renal proximal tubule [http://www.ncbi.nlm.nih.gov/pubmed/19033659?dopt=AbstractPlus] and at the plasma‐membrane in brown/beige adipocytes [http://www.ncbi.nlm.nih.gov/pubmed/25080478?dopt=AbstractPlus]. PAT1 and PAT4 are involved in regulation of the mTORC1 pathway [http://www.ncbi.nlm.nih.gov/pubmed/29971004?dopt=AbstractPlus]. More comprehensive lists of substrates can be found within the reviews under Further Reading and in the references.
Further reading on SLC36 family of proton‐coupled amino acid transporters
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 https://www.ncbi.nlm.nih.gov/pubmed/23506890?dopt=AbstractPlus
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 https://www.ncbi.nlm.nih.gov/pubmed/21501141?dopt=AbstractPlus
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 https://www.ncbi.nlm.nih.gov/pubmed/17123464?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=224
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.
Further reading on SLC37 family of phosphosugar/phosphate exchangers
Chou JY et al. (2014) The SLC37 family of sugar‐phosphate/phosphate exchangers. Curr Top Membr 73: 357–82 https://www.ncbi.nlm.nih.gov/pubmed/24745989?dopt=AbstractPlus
Chou JY et al. (2013) The SLC37 family of phosphate‐linked sugar phosphate antiporters. Mol. Aspects Med. 34: 601–11 https://www.ncbi.nlm.nih.gov/pubmed/23506893?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=150
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 [http://www.ncbi.nlm.nih.gov/pubmed/23506890?dopt=AbstractPlus].
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=225
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=226
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=227
| Nomenclature | http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1175 |
| Systematic nomenclature | SLC38A7 |
| Common abbreviation | SNAT7 |
| HGNC, UniProt | https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:25582, http://www.uniprot.org/uniprot/Q9NVC3 |
| Comments | SNAT7/SLC38A7 has been described to be a system N‐like transporter allowing preferential accumulation of glutamine (e.g. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=723), histidine (e.g. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3310) and asparagine (e.g. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4533) [http://www.ncbi.nlm.nih.gov/pubmed/21511949?dopt=AbstractPlus]. |
Further reading on SLC38 family of sodium‐dependent neutral amino acid transporters
Bhutia YD et al. (2016) Glutamine transporters inmammalian cells and their functions in physiology and cancer. Biochim. Biophys. Acta 1863: 2531–9 https://www.ncbi.nlm.nih.gov/pubmed/26724577?dopt=AbstractPlus
Bröer S. (2014) The SLC38 family of sodium‐amino acid co‐transporters. Pflugers Arch. 466: 155–72 https://www.ncbi.nlm.nih.gov/pubmed/24193407?dopt=AbstractPlus
Bröer S et al. (2011) The role of amino acid transporters in inherited and acquired diseases. Biochem. J. 436: 193–211 https://www.ncbi.nlm.nih.gov/pubmed/21568940?dopt=AbstractPlus
Hägglund MG et al. (2011) Identification of SLC38A7 (SNAT7) protein as a glutamine transporter expressed in neurons. J. Biol. Chem. 286: 20500–11 https://www.ncbi.nlm.nih.gov/pubmed/21511949?dopt=AbstractPlus
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 https://www.ncbi.nlm.nih.gov/pubmed/23506890?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=228
Overview
Along with the http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=217, 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 [http://www.ncbi.nlm.nih.gov/pubmed/18270315?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/18037372?dopt=AbstractPlus].
Comments
Zinc fluxes may be monitored through the use of radioisotopic Zn‐65 or the fluorescent dye FluoZin 3. The bicarbonate transport inhibitor http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4177 has been reported to inhibit cation accumulation through ZIP14 [http://www.ncbi.nlm.nih.gov/pubmed/18270315?dopt=AbstractPlus].
Further reading on SLC39 family of metal ion transporters
Hojyo S et al. (2016) Zinc transporters and signaling in physiology and pathogenesis. Arch. Biochem. Biophys. 611: 43–50 https://www.ncbi.nlm.nih.gov/pubmed/27394923?dopt=AbstractPlus
Jeong J et al. (2013) The SLC39 family of zinc transporters. Mol. Aspects Med. 34: 612–9 https://www.ncbi.nlm.nih.gov/pubmed/23506894?dopt=AbstractPlus
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 https://www.ncbi.nlm.nih.gov/pubmed/24710731?dopt=AbstractPlus
Kambe T et al. (2015) The Physiological, Biochemical, and Molecular Roles of Zinc Transporters in Zinc Homeostasis and Metabolism. Physiol. Rev. 95: 749–784 https://www.ncbi.nlm.nih.gov/pubmed/26084690?dopt=AbstractPlus
Marger L et al. (2014) Zinc: an underappreciated modulatory factor of brain function. Biochem. Pharmacol. 91: 426–35 https://www.ncbi.nlm.nih.gov/pubmed/25130547?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=229
Overview
Alongside the http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=183 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 [http://www.ncbi.nlm.nih.gov/pubmed/19150361?dopt=AbstractPlus], with the functional transporter potentially a dimeric arrangement [http://www.ncbi.nlm.nih.gov/pubmed/15667655?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/17077321?dopt=AbstractPlus]. Ferroportin is essential for iron homeostasis [http://www.ncbi.nlm.nih.gov/pubmed/16054062?dopt=AbstractPlus]. 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 antianemia agents. Anti‐ferroportin monoclonal antibodies are such an agent.
| Nomenclature | http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1194 |
| Systematic nomenclature | SLC40A1 |
| Common abbreviation | IREG1 |
| HGNC, UniProt | https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:10909, http://www.uniprot.org/uniprot/Q9NP59 |
| Endogenous substrates | Fe2+ |
| Stoichiometry | Unknown |
| Antibodies | http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=8416 (Binding) [395] |
Comments
Hepcidin (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:15598, http://www.uniprot.org/uniprot/P81172), cleaved into http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5378 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:15598, http://www.uniprot.org/uniprot/P81172) and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5379 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:15598, http://www.uniprot.org/uniprot/P81172), 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 [http://www.ncbi.nlm.nih.gov/pubmed/16054062?dopt=AbstractPlus], while loss‐of‐function mutations in man are associated with haemochromatosis [http://www.ncbi.nlm.nih.gov/pubmed/15956209?dopt=AbstractPlus].
Further reading on SLC40 iron transporter
McKie AT et al. (2004) The SLC40 basolateral iron transporter family (IREG1/ferroportin/MTP1). Pflugers Arch. 447: 801–6 https://www.ncbi.nlm.nih.gov/pubmed/12836025?dopt=AbstractPlus
Montalbetti N et al. (2013) Mammalian iron transporters: families SLC11 and SLC40. Mol. Aspects Med. 34: 270–87 https://www.ncbi.nlm.nih.gov/pubmed/23506870?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=230
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 [http://www.ncbi.nlm.nih.gov/pubmed/22031603?dopt=AbstractPlus], possibly as a result of co‐expression of particular protein partners (see [http://www.ncbi.nlm.nih.gov/pubmed/23506895?dopt=AbstractPlus]). Topological modelling suggests 10 TM domains with cytoplasmic C‐ and N‐ termini.
Further reading on SLC41 family of divalent cation transporters
Payandeh J et al. (2013) The structure and regulation of magnesium selective ion channels. Biochim. Biophys. Acta 1828: 2778‐92 https://www.ncbi.nlm.nih.gov/pubmed/23954807?dopt=AbstractPlus
Sahni J et al. (2013) The SLC41 family of MgtE‐like magnesium transporters. Mol. Aspects Med. 34: 620‐8 https://www.ncbi.nlm.nih.gov/pubmed/23506895?dopt=AbstractPlus
Schweigel‐Röntgen M et al. (2014) SLC41 transporters–molecular identification and functional role. Curr Top Membr 73: 383‐410 https://www.ncbi.nlm.nih.gov/pubmed/24745990?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=231
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, https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:10008 (http://www.uniprot.org/uniprot/P18577) and https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:10009 (http://www.uniprot.org/uniprot/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.
Further reading on SLC42 family of Rhesus glycoprotein ammonium transporters
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 https://www.ncbi.nlm.nih.gov/pubmed/23506896?dopt=AbstractPlus
Weiner ID et al. (2011) Role of NH3 and NH4 + transporters in renal acid‐base transport. Am. J. Physiol. Renal Physiol. 300: F11‐23 https://www.ncbi.nlm.nih.gov/pubmed/21048022?dopt=AbstractPlus
Weiner ID et al. (2014) Ammonia transport in the kidney by Rhesus glycoproteins. Am. J. Physiol. Renal Physiol. 306: F1107‐20 https://www.ncbi.nlm.nih.gov/pubmed/24647713?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=232
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 http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=141#SLC7 family. LAT3 and LAT4 contain 12 put.ative 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 [http://www.ncbi.nlm.nih.gov/pubmed/12930836?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/15659399?dopt=AbstractPlus]. LAT3/SLC43A1 is expressed in human tissues at high levels in the pancreas, liver, skeletal muscle and fetal liver [http://www.ncbi.nlm.nih.gov/pubmed/12930836?dopt=AbstractPlus] whereas LAT4/SLC43A2 is primarily expressed in the placenta, kidney and peripheral blood leukocytes [http://www.ncbi.nlm.nih.gov/pubmed/15659399?dopt=AbstractPlus]. SLC43A3 is expressed in vascular endothelial cells [http://www.ncbi.nlm.nih.gov/pubmed/18483404?dopt=AbstractPlus] but remains to be characterised.
Comments
Covalent modification of LAT3 by http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5335 inhibits its function [http://www.ncbi.nlm.nih.gov/pubmed/12930836?dopt=AbstractPlus] and at LAT4 inhibits the low‐, but not high‐affinity component of transport [http://www.ncbi.nlm.nih.gov/pubmed/15659399?dopt=AbstractPlus].
Further reading on SLC43 family of large neutral amino acid transporters
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 https://www.ncbi.nlm.nih.gov/pubmed/23268354?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=233
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 [http://www.ncbi.nlm.nih.gov/pubmed/15715662?dopt=AbstractPlus]. CTL family members are putative 10TM domain proteins with extracellular termini that mediate Na+‐independent transport of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4551 with an affinity that is intermediate to that of the high affinity choline transporter CHT1 (http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=143#show_object_914) and the low affinity organiccation transporters [OCT1 (http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=146#show_object_1019) andOCT2 (http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=146#show_object_1020)] [http://www.ncbi.nlm.nih.gov/pubmed/16636297?dopt=AbstractPlus]. CLT1 is expressed almost ubiquitously in human tissues [http://www.ncbi.nlm.nih.gov/pubmed/11698453?dopt=AbstractPlus] and mediates http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4551 transport across the plasma and mitochondrial membranes [http://www.ncbi.nlm.nih.gov/pubmed/19357133?dopt=AbstractPlus]. Transport of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4551 by CTL2, which in rodents is expressed as two isoforms (CTL2P1 and CLTP2; [http://www.ncbi.nlm.nih.gov/pubmed/20665236?dopt=AbstractPlus]) in lung, colon, inner ear and spleen and to a lesser extent in brain, tongue, liver, and kidney, has only recently been demonstrated [http://www.ncbi.nlm.nih.gov/pubmed/20665236?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/20410607?dopt=AbstractPlus]. CTL3‐5 remain to be characterized functionally.
| Nomenclature | http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1204 |
| Systematic nomenclature | SLC44A1 |
| Common abbreviation | CTL1 |
| HGNC, UniProt | https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:18798, http://www.uniprot.org/uniprot/Q8WWI5 |
| Substrates | http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4551 |
| 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 | http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4494 (pK i 3.5–4.5) |
Comments
Data tabulated are features observed for CLT1 endogenous to: rat astrocytes [http://www.ncbi.nlm.nih.gov/pubmed/16000150?dopt=AbstractPlus]; rat renal tubule epithelial cells [http://www.ncbi.nlm.nih.gov/pubmed/19236841?dopt=AbstractPlus]; human colon carcinoma cells [http://www.ncbi.nlm.nih.gov/pubmed/19135976?dopt=AbstractPlus]; human keratinocytes [http://www.ncbi.nlm.nih.gov/pubmed/19122366?dopt=AbstractPlus] and human neuroblastoma cells [http://www.ncbi.nlm.nih.gov/pubmed/21185344?dopt=AbstractPlus]. Choline uptake by CLT1 is inhibited by numerous organic cations (e.g. [http://www.ncbi.nlm.nih.gov/pubmed/16000150?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/19236841?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/21185344?dopt=AbstractPlus]). In the guinea‐pig, CTL2 is a target for antibody‐induced hearing loss [http://www.ncbi.nlm.nih.gov/pubmed/14973250?dopt=AbstractPlus] and in man, a polymorphism in CTL2 constitutes the human neutrophil alloantigen‐3a (HNA‐3a; [http://www.ncbi.nlm.nih.gov/pubmed/20037594?dopt=AbstractPlus]).
Further reading on SLC44 choline transporter‐like family
Inazu M. (2014) Choline transporter‐like proteins CTLs/SLC44 family as a novel molecular target for cancer therapy. Biopharm Drug Dispos 35: 431‐49 https://www.ncbi.nlm.nih.gov/pubmed/24532461?dopt=AbstractPlus
Traiffort E et al. (2013) The choline transporter‐like family SLC44: properties and roles in human diseases. Mol. Aspects Med. 34: 646‐54 https://www.ncbi.nlm.nih.gov/pubmed/23506897?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=234
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 [http://www.ncbi.nlm.nih.gov/pubmed/12417639?dopt=AbstractPlus]. The protein is predicted to have 12TM domains, with intracellular termini. The SLC45A2 gene is thought to encode a transporter protein that mediates http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5415 synthesis. Mutations in SLC45A2 are a cause of oculocutaneous albinism type 4 (e.g. [http://www.ncbi.nlm.nih.gov/pubmed/11574907?dopt=AbstractPlus]), and polymorphisms in this gene are associated with variations in skin and hair color (e.g. [http://www.ncbi.nlm.nih.gov/pubmed/15714523?dopt=AbstractPlus]).
| Nomenclature | http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1209 |
| Systematic nomenclature | SLC45A1 |
| HGNC, UniProt | https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:17939, http://www.uniprot.org/uniprot/Q9Y2W3 |
| Substrates | http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4719 [http://www.ncbi.nlm.nih.gov/pubmed/12417639?dopt=AbstractPlus], Galactose [http://www.ncbi.nlm.nih.gov/pubmed/12417639?dopt=AbstractPlus] |
| Stoichiometry | Unknown; increased at acid pH [http://www.ncbi.nlm.nih.gov/pubmed/12417639?dopt=AbstractPlus]. |
Further reading on SLC45 family of putative sugar transporters
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 https://www.ncbi.nlm.nih.gov/pubmed/25164149?dopt=AbstractPlus
Vitavska O et al. (2013) The SLC45 gene family of putative sugar transporters. Mol. Aspects Med. 34: 655‐60 https://www.ncbi.nlm.nih.gov/pubmed/23506898?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=235
Overview
Based on the proptypicalmember of this family, PCFT, this family includes proton‐driven transporters with 11 TMsegments. SLC46A1 has been described to act as an intestinal proton‐coupled high‐affinity http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4563 transporter [http://www.ncbi.nlm.nih.gov/pubmed/17129779?dopt=AbstractPlus], with lower affinity for http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4349. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4563 accumulation is independent of Na+ or K+ ion concentrations, but driven by extracellular protons with an as yet undefined stoichiometry.
Further reading on SLC46 family of folate transporters
Hou Z et al. (2014) Biology of the major facilitative folate transporters SLC19A1 and SLC46A1. Curr Top Membr 73: 175‐204 https://www.ncbi.nlm.nih.gov/pubmed/24745983?dopt=AbstractPlus
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 https://www.ncbi.nlm.nih.gov/pubmed/24396145?dopt=AbstractPlus
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. 469: 33‐44 https://www.ncbi.nlm.nih.gov/pubmed/25877470?dopt=AbstractPlus
Zhao R et al. (2011) Mechanisms of membrane transport of folates into cells and across epithelia. Annu. Rev. Nutr. 31: 177‐201 https://www.ncbi.nlm.nih.gov/pubmed/21568705?dopt=AbstractPlus
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 https://www.ncbi.nlm.nih.gov/pubmed/23506878?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=236
Overview
These proton:organic cation exchangers are predicted to have 13 TM segments [http://www.ncbi.nlm.nih.gov/pubmed/19515813?dopt=AbstractPlus] and are suggested to be responsible for excretion of many drugs in the liver and kidneys.
Comments
DAPI has been used to allow quantification of MATE1 and MATE2‐mediated transport activity [http://www.ncbi.nlm.nih.gov/pubmed/20047987?dopt=AbstractPlus]. MATE2 and MATE2‐B are inactive splice variants of MATE2‐K [http://www.ncbi.nlm.nih.gov/pubmed/16807400?dopt=AbstractPlus].
Further reading on SLC47 family of multidrug and toxin extrusion transporters
Damme K et al. (2011) Mammalian MATE (SLC47A) transport proteins: impact on efflux of endogenous substrates and xenobiotics. Drug Metab. Rev. 43: 499‐523 https://www.ncbi.nlm.nih.gov/pubmed/21923552?dopt=AbstractPlus
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 https://www.ncbi.nlm.nih.gov/pubmed/23506899?dopt=AbstractPlus
Nies AT et al. (2016) Structure and function of multidrug and toxin extrusion proteins (MATEs) and their relevance to drug therapy and personalized medicine. Arch. Toxicol. 90: 1555‐84 https://www.ncbi.nlm.nih.gov/pubmed/27165417?dopt=AbstractPlus
Wagner DJ et al. (2016) Polyspecific organic cation transporters and their impact on drug intracellular levels and pharmacodynamics. Pharmacol. Res. 111: 237‐246 https://www.ncbi.nlm.nih.gov/pubmed/27317943?dopt=AbstractPlus
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 https://www.ncbi.nlm.nih.gov/pubmed/21457222?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=237
Overview
HRG1 has been identified as a cell surface and lysosomal heme transporter [http://www.ncbi.nlm.nih.gov/pubmed/18418376?dopt=AbstractPlus]. In addition, evidence suggests this 4TM‐containing protein associates with the http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=137#V‐type ATPase in lysosomes [http://www.ncbi.nlm.nih.gov/pubmed/19875448?dopt=AbstractPlus]. 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 [http://www.ncbi.nlm.nih.gov/pubmed/23395172?dopt=AbstractPlus].
| Nomenclature | http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1218 |
| Systematic nomenclature | SLC48A1 |
| Common abbreviation | HRG1 |
| HGNC, UniProt | https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:26035, http://www.uniprot.org/uniprot/Q6P1K1 |
Further reading on SLC48 heme transporter
Khan AA et al. (2013) Heme and FLVCR‐related transporter families SLC48 and SLC49. Mol. Aspects Med. 34: 669‐82 https://www.ncbi.nlm.nih.gov/pubmed/23506900?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=335
Overview
FLVCR1 was initially identified as a cell‐surface attachment site for feline leukemia virus subgroup C [http://www.ncbi.nlm.nih.gov/pubmed/10400745?dopt=AbstractPlus], and later identified as a cell surface accumulation which exports heme from the cytosol [http://www.ncbi.nlm.nih.gov/pubmed/15369674?dopt=AbstractPlus]. 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 [http://www.ncbi.nlm.nih.gov/pubmed/23187127?dopt=AbstractPlus]. FLVCR‐mediated heme transport is essential for erythropoiesis. Flvcr1 gene mutations have been identified as the cause of PCARP (http://www.omim.org/entry/609033?search=609033&highlight=609033 (PCARP) [http://www.ncbi.nlm.nih.gov/pubmed/21070897?dopt=AbstractPlus].There are three paralogs of FLVCR1 in the human genome.
FLVCR2, most similar to FLVCR1 [http://www.ncbi.nlm.nih.gov/pubmed/11943475?dopt=AbstractPlus], has been reported to function as a heme importer [http://www.ncbi.nlm.nih.gov/pubmed/20823265?dopt=AbstractPlus]. 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 [http://www.ncbi.nlm.nih.gov/pubmed/20206334?dopt=AbstractPlus].
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 [http://www.ncbi.nlm.nih.gov/pubmed/11912179?dopt=AbstractPlus].
Comments
Non‐functional splice alternatives of FLVCR1 have been implicated as a cause of a congenital red cell aplasia, http://omim.org/entry/105650 [http://www.ncbi.nlm.nih.gov/pubmed/18815190?dopt=AbstractPlus].
Further reading on SLC49 family of FLVCR‐related heme transporters
Khan AA et al. (2013) Heme and FLVCR‐related transporter families SLC48 and SLC49. Mol. Aspects Med. 34: 669‐82 https://www.ncbi.nlm.nih.gov/pubmed/23506900?dopt=AbstractPlus
Khan AA et al. (2011) Control of intracellular heme levels: heme transporters and heme oxygenases. Biochim. Biophys. Acta 1813: 668‐82 https://www.ncbi.nlm.nih.gov/pubmed/21238504?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=336
Overview
A mouse stromal cell cDNA library was used to clone C2.3 [http://www.ncbi.nlm.nih.gov/pubmed/8630032?dopt=AbstractPlus], 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 http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4536 [http://www.ncbi.nlm.nih.gov/pubmed/21107422?dopt=AbstractPlus]. Expression of mouse SWEET in the mammary gland was suggestive of a role in Golgi lactose synthesis [http://www.ncbi.nlm.nih.gov/pubmed/21107422?dopt=AbstractPlus].
| Nomenclature | http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1914 |
| Systematic nomenclature | SLC50A1 |
| Common abbreviation | RAG1AP1 |
| HGNC, UniProt | https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:30657, http://www.uniprot.org/uniprot/Q9BRV3 |
Further reading on SLC50 sugar transporter
Wright EM. (2013) Glucose transport families SLC5 and SLC50. Mol. Aspects Med. 34: 183‐96 https://www.ncbi.nlm.nih.gov/pubmed/23506865?dopt=AbstractPlus
Wright EM et al. (2011) Biology of human sodium glucose transporters. Physiol. Rev. 91: 733‐94 https://www.ncbi.nlm.nih.gov/pubmed/21527736?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=337
Overview
The SLC51 organic solute transporter family of transporters is a pair of heterodimeric proteins which regulate bile salt movements in the small intestine, bile duct, and liver, as part of the enterohepatic circulation [http://www.ncbi.nlm.nih.gov/pubmed/16317684?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/15563450?dopt=AbstractPlus]. OSTα/OSTβ is also expressed in steroidogenic cells of the brain and adrenal gland, where it may contribute to steroid movement [http://www.ncbi.nlm.nih.gov/pubmed/20649839?dopt=AbstractPlus]. Bile acid transport is suggested to be facilitative and independent of sodium, potassium, chloride ions or protons [http://www.ncbi.nlm.nih.gov/pubmed/16317684?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/15563450?dopt=AbstractPlus]. OSTα/OSTβ heterodimers have been shown to transport http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4546, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5577, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4748, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6504 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5577 [http://www.ncbi.nlm.nih.gov/pubmed/16317684?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/15563450?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/20649839?dopt=AbstractPlus]. OSTα/OSTβ‐mediated transport of bile salts is inhibited by http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=9184 [http://www.ncbi.nlm.nih.gov/pubmed/29675448?dopt=AbstractPlus]. 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 [http://www.ncbi.nlm.nih.gov/pubmed/17650074?dopt=AbstractPlus]. Both proteins function in solute transport and bimolecular fluorescence complementation studies suggest the possibility of OSTα homooligomers, as well as OSTα/OSTβ hetero‐oligomers [http://www.ncbi.nlm.nih.gov/pubmed/22535958?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/17650074?dopt=AbstractPlus]. An inherited mutation in OSTβ is associated with congenital diarrhea in children [http://www.ncbi.nlm.nih.gov/pubmed/28898457?dopt=AbstractPlus].
| Nomenclature | http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1915 | http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1916 |
| Systematic nomenclature | SLC51A1 | SLC51B |
| Common abbreviation | OSTα | OSTβ |
| HGNC, UniProt | https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:29955, http://www.uniprot.org/uniprot/Q86UW1 | https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:29956, http://www.uniprot.org/uniprot/Q86UW2 |
Further reading on SLC51 family of steroid‐derived molecule transporters
Ballatori N. (2011) Pleiotropic functions of the organic solute transporter Ostα‐Ostβ. Dig Dis 29: 13‐7 https://www.ncbi.nlm.nih.gov/pubmed/21691099?dopt=AbstractPlus
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 https://www.ncbi.nlm.nih.gov/pubmed/23506901?dopt=AbstractPlus
Dawson PA. (2011) Role of the intestinal bile acid transporters in bile acid and drug disposition. Handb Exp Pharmacol 169‐203 https://www.ncbi.nlm.nih.gov/pubmed/21103970?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=786
Overview
http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6578, also known as vitamin B2, is a precursor of the enzyme cofactors http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5185 (FMN) and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5184 (FAD). Riboflavin transporters are predicted to possess 10 or 11 TM segments.
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 on SLC52 family of riboflavin transporters
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 [https://www.ncbi.nlm.nih.gov/pubmed/23506902?dopt=AbstractPlus]
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=1005
| Nomenclature | http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=3021 |
| Systematic nomenclature | SLC53A1 |
| HGNC, UniProt | https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:12827, http://www.uniprot.org/uniprot/Q9UBH6 |
| Substrates | Phosphate [http://www.ncbi.nlm.nih.gov/pubmed/23791524?dopt=AbstractPlus] |
| Comments | XPR1/SLC53A1 is a phosphate carrier which appears to play a role in bone and tooth mineralization. It is ubiquitously expressed [http://www.ncbi.nlm.nih.gov/pubmed/9990033?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/9927670?dopt=AbstractPlus]. The pathological consequences of defective SLC53A1 expression in the brain [http://www.ncbi.nlm.nih.gov/pubmed/25938945?dopt=AbstractPlus] and kidney [http://www.ncbi.nlm.nih.gov/pubmed/27799484?dopt=AbstractPlus] have been reported. |
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=1006
Comments
SLC54 family transporters appear to function as mechanisms for accumulating pyruvate into mitochondria to link glycolysis with oxidative phosphorylation.
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=1007
Comments
The family of SLC55 mitochondrial transporters appear to regulate ion fluxes and to maintain tubular networks.
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=1008
Comments
These are a family of incompletely‐characterised mitochondrial transporters.
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=1009
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=1010
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=1011
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=1012
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=1013
| Nomenclature | http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=3045 |
| Systematic nomenclature | SLC61A1 |
| HGNC, UniProt | https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:28156, http://www.uniprot.org/uniprot/Q6N075 |
| Substrates | molybdate [http://www.ncbi.nlm.nih.gov/pubmed/21464289?dopt=AbstractPlus] |
| Comments | MFSD5/SLC61 is a putative 12TM cell‐surface protein which appears to allow the accumulation of molybdate, and where the neural expression appears to respond to changes in the diet. It is expressed in cervix, stomach, nerve and skin [http://www.ncbi.nlm.nih.gov/pubmed/21464289?dopt=AbstractPlus]; ubiquitous but higher in skeletal muscle, olfactory bulb [http://www.ncbi.nlm.nih.gov/pubmed/18948099?dopt=AbstractPlus]; blood, cortex, hypothalamus, cerebellum and spinal cord (mouse) [http://www.ncbi.nlm.nih.gov/pubmed/27272503?dopt=AbstractPlus]. |
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=1014
| Nomenclature | http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=3046 |
| Systematic nomenclature | SLC62A1 |
| HGNC, UniProt | https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:15492, Qhttp://www.uniprot.org/uniprot/Q9HCJ1 |
| Substrates | Pyrophosphate [http://www.ncbi.nlm.nih.gov/pubmed/10894769?dopt=AbstractPlus] |
| Comments | ANKH/SLC62 is a putative 8TM membrane protein, also known as progressive ankylosis protein homolog. Mutations in this protein are associated with bone and joint abnormalities. It is expressed in kidney and bone [http://www.ncbi.nlm.nih.gov/pubmed/19910700?dopt=AbstractPlus]. |
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=1015
Overview
The SLC63 family of transporters has roles inside the cell (SLC63A1/SPNS1) or on the cell surface (SLC63A2/SPNS2) in sphingolipid transport.
| Nomenclature | http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=3047 |
| Systematic nomenclature | SLC63A1 |
| HGNC, UniProt | https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:30621, http://www.uniprot.org/uniprot/Q9H2V7 |
| Comments | Expressed in mitochondria [http://www.ncbi.nlm.nih.gov/pubmed/12815463?dopt=AbstractPlus]. |
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=1016
| Nomenclature | http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=3050 |
| Systematic nomenclature | SLC64A1 |
| HGNC, UniProt | https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:30760, http://www.uniprot.org/uniprot/Q9HC07 |
| Transport type | Exchanger/ Ca2+:H+ |
| Substrates | Mn2+ [http://www.ncbi.nlm.nih.gov/pubmed/28270545?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/27008884?dopt=AbstractPlus], Ca2+, H+ [http://www.ncbi.nlm.nih.gov/pubmed/23569283?dopt=AbstractPlus] |
| Comments | TMEM165/SLC64 is a putative 6TM intracellular membrane protein. Mutations in the protein are associated with congenital disorder of glycosylation. It has been suggested to be essential for milk production in the mammary gland [http://www.ncbi.nlm.nih.gov/pubmed/30622138?dopt=AbstractPlus]. TMEM165 deficiency (via siRNA knockdown) causes Golgi glycosylation defects in transfected HEK cells [http://www.ncbi.nlm.nih.gov/pubmed/22683087?dopt=AbstractPlus]. |
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=1017
Overview
The SLC65 family of intracellular cholesterol transporters are 13TM membrane proteins. NPC1/SLC65A1 is an intracellular cholesterol transporter, which together with NPC2 (Uniprot ID https://www.uniprot.org/uniprot/P61916), allows the accumulation into the cytosol of cholesterol acquired from low density lipoproteins.
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=238
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.
Further reading on SLCO family of organic anion transporting polypeptides
Hagenbuch B et al. (2013) The SLCO (former SLC21) superfamily of transporters. Mol. Aspects Med. 34: 396‐412 https://www.ncbi.nlm.nih.gov/pubmed/23506880?dopt=AbstractPlus
Hillgren KM et al. (2013) Emerging transporters of clinical importance: an update from the International Transporter Consortium. Clin. Pharmacol. Ther. 94: 52‐63 https://www.ncbi.nlm.nih.gov/pubmed/23588305?dopt=AbstractPlus
International Transporter Consortium et al. (2010) Membrane transporters in drug development. Nat Rev Drug Discov 9: 215‐36 https://www.ncbi.nlm.nih.gov/pubmed/20190787?dopt=AbstractPlus
Lee HH et al. (2017) Interindividual and interethnic variability in drug disposition: polymorphisms in organic anion transporting polypeptide 1B1 (OATP1B1; SLCO1B1). Br J Clin Pharmacol 83: 1176‐1184 https://www.ncbi.nlm.nih.gov/pubmed/27936281?dopt=AbstractPlus
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 https://www.ncbi.nlm.nih.gov/pubmed/22013971?dopt=AbstractPlus
Zamek‐Gliszczynski MJ et al. (2018) Transporters in Drug Development: 2018 ITC Recommendations for Transporters of Emerging Clinical Importance. Clin. Pharmacol. Ther. 104: 890‐899 https://www.ncbi.nlm.nih.gov/pubmed/30091177?dopt=AbstractPlus
Further reading on SLC superfamily of solute carriers
Bhutia YD et al. (2016) SLC transporters as a novel class of tumour suppressors: identity, function and molecular mechanisms. Biochem. J. 473: 1113‐24 https://www.ncbi.nlm.nih.gov/pubmed/27118869?dopt=AbstractPlus
Colas C et al. (2016) SLC Transporters: Structure, Function, and Drug Discovery. Medchemcomm 7: 1069‐1081 https://www.ncbi.nlm.nih.gov/pubmed/27672436?dopt=AbstractPlus
César‐Razquin A et al. (2015) A Call for Systematic Research on Solute Carriers. Cell 162: 478‐87 https://www.ncbi.nlm.nih.gov/pubmed/26232220?dopt=AbstractPlus
Lin L et al. (2015) SLC transporters as therapeutic targets: emerging opportunities. Nat Rev Drug Discov 14: 543‐60 https://www.ncbi.nlm.nih.gov/pubmed/26111766?dopt=AbstractPlus
Naa|cz KA. (2017) Solute Carriers in the Blood‐Brain Barier: Safety in Abundance. Neurochem. Res. 42: 795‐809 https://www.ncbi.nlm.nih.gov/pubmed/27503090?dopt=AbstractPlus
Neul C et al. (2016) Impact of Membrane Drug Transporters on Resistance to Small‐Molecule Tyrosine Kinase Inhibitors. Trends Pharmacol. Sci. 37: 904‐932 https://www.ncbi.nlm.nih.gov/pubmed/27659854?dopt=AbstractPlus
Nigam SK. (2015) What do drug transporters really do? Nat Rev Drug Discov 14: 29‐44 https://www.ncbi.nlm.nih.gov/pubmed/25475361?dopt=AbstractPlus
Pedersen NB et al. (2016) Glycosylation of solute carriers: mechanisms and functional consequences. Pflugers Arch. 468: 159‐76 https://www.ncbi.nlm.nih.gov/pubmed/26383868?dopt=AbstractPlus
Perland E et al. (2017) Classification Systems of Secondary Active Transporters. Trends Pharmacol. Sci. 38: 305‐315 https://www.ncbi.nlm.nih.gov/pubmed/27939446?dopt=AbstractPlus
Rives ML et al. (2017) Potentiating SLC transporter activity: Emerging drug discovery opportunities. Biochem. Pharmacol. 135: 1‐11 https://www.ncbi.nlm.nih.gov/pubmed/28214518?dopt=AbstractPlus
Alexander Stephen PH, Kelly Eamonn, Mathie Alistair, Peters John A, Veale Emma L, Armstrong Jane F, Faccenda Elena, Harding Simon D, Pawson Adam J, Sharman Joanna L, Southan Christopher, Davies Jamie A and CGTP Collaborators (2019) THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: Transporters. British Journal of Pharmacology, 176: S397–S493. doi: 10.1111/bph.14753.
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