Transporters

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 and 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 not only a great variety of solutes transported, from simple inorganic ions to amino acids and sugars to relatively complex organic molecules like haem. The solute carrier family includes 48 families of almost 400 members, many of whom remain orphan transporters, in as much as a physiological function has yet to be determined. The SLC transporters include members which function as antiports, where solute movement in one direction is balanced by a solute moving in the reverse direction. Symports allow concentration gradients of one solute to allow movement of a second solute across a membrane. A third, relatively small group are equilibrative transporters, which allow solutes to travel across membranes down their concentration gradients. A more complex family of transporters, the SLC27 fatty acid transporters also express enzymatic function. Many of the transporters also express electrogenic properties of ion channels.

ATP-binding cassette family

Overview: ATP-binding cassette transporters are ubiquitous membrane proteins characterized by facilitated movement of a range of substrates, including ions, lipids, peptides, steroids. The functional transporter is probably dimeric, with individual subunits 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, appear relatively truncated 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.

ABCA subfamily

Systematic name	Common abbreviation	Other names	Ensembl ID	Comments
ABCA1	ABC1, CERP	Cholesterol efflux regulatory protein	ENSG00000165029	Loss-of-function mutations are associated with Tangier disease, in which plasma HDL cholesterol levels are greatly reduced
ABCA2	ABC2	–	ENSG00000107331	–
ABCA3	ABC3, ABCC	–	ENSG00000167972	Loss-of-function mutations are associated with pulmonary surfactant deficiency
ABCA4	ABCR	Retinal-specific ATP-binding cassette transporter, RIM ABC transporter, RmP, Stargardt disease protein	ENSG00000198691	Retinal-specific transporter of N-retinylPE; loss-of-function mutations are associated with Stargardt disease, a juvenile onset macular degenerative disease
ABCA5	–	–	ENSG00000154265	–
ABCA6	–	–	ENSG00000154262	–
ABCA7	–	–	ENSG00000064687	Genome wide association studies identify ABCA7 variants as associated with Alzheimer's Disease (Hollingworth et al., 2011)
ABCA8	–	KIAA0822	ENSG00000141338	–
ABCA9	–	–	ENSG00000154258	–
ABCA10	–	–	ENSG00000154263	–
ABCA12	–	–	ENSG00000144452	Reported to play a role in skin ceramide formation (Zuo et al., 2008)
ABCA13	–	–	ENSG00000179869	–

A number of structural analogues are not found in man: ABCA14 (ENSMUSG00000062017); ABCA15 (ENSMUSG00000054746); ABCA16 (ENSMUSG00000051900) and ABCA17 (ENSMUSG00000035435).

ABCB subfamily

Systematic name	Common abbreviation	Other names	Ensembl ID	Comments
ABCB1	MDR1, PGP1	Multi-drug resistance protein 1, P-glycoprotein 1, CD243 antigen	ENSG00000085563	Responsible for the cellular export of many therapeutic drugs
ABCB2	TAP1	Antigen peptide transporter 1, APT1, peptide transporter TAP1, peptide supply factor 1 (PSF-1), peptide transporter involved in antigen processing 1	ENSG00000168394	Endoplasmic reticulum, possibly as heterodimer with TAP2
ABCB3	TAP2	Antigen peptide transporter 2 (APT2), Peptide transporter TAP2, peptide supply factor 2 (PSF-2), peptide transporter involved in antigen processing 2	ENSG00000204267	Endoplasmic reticulum, possibly as heterodimer with TAP1
ABCB4	PGY3	Multi-drug resistance protein 3, P-glycoprotein 3	ENSG00000005471	Transports phosphatidylcholine from intracellular to extracellular face of the hepatocyte canalicular membrane (Oude Elferink and Paulusma, 2007)
ABCB5	–	–	ENSG00000004846	Multidrug resistance protein in, and marker of, melanoma cells (Schatton et al. 2008)
ABCB6	MTABC3	Mitochondrial ABC transporter 3, ubiquitously expressed mammalian ABC half transporter, P-glycoprotein-related protein	ENSG00000115657	Mitochondrial porphyrin transporter (Krishnamurthy et al., 2006)
ABCB7	ABC7	–	ENSG00000131269	Mitochondrial; reportedly essential for haematopoiesis (Pondarre et al., 2007)
ABCB8	MABC1	–	ENSG00000197150	Mitochondrial; suggested to play a role in chemoresistance of melanoma (Elliott and Al-Hajj, 2009)
ABCB9	TAPL	TAP-like protein, hABCB9	ENSG00000150967	Reported to be lysosomal (Kamakura et al., 2008)
ABCB10	MTABC2	Mitochondrial ABC transporter 2	ENSG00000135776	Mitochondrial
ABCB11	ABC16	Bile salt export pump, BSEP, PFIC-2, PFIC2, PGY4, SPGP	ENSG00000073734	Loss-of-function mutations are associated with familial intrahepatic cholestasis (Stieger, 2009)

ABCC subfamily

Systematic name	Common abbreviation	Other names	Ensembl ID	Comments
ABCC1	MRP1	Multidrug resistance-associated protein 1, leukotriene C4 transporter	ENSG00000103222	Exhibits a broad substrate specificity (Bakos and Homolya, 2007)
ABCC2	MRP2, cMOAT	Multidrug resistance-associated protein 2, canalicular multispecific organic anion transporter 1, canalicular multidrug resistance protein	ENSG00000023839	Loss-of-function mutations are associated with Dubin-Johnson syndrome, in which plasma levels of conjugated bilirubin are elevated
ABCC3	MRP3	Multidrug resistance-associated protein 3, canalicular multispecific organic anion transporter 2, multi-specific organic anion transporter-D, MOAT-D	ENSG00000108846	Transports conjugates of glutathione, sulfate or glucuronide (see Borst et al., 2007)
ABCC4	MRP4	Multidrug resistance-associated protein 4, multi-specific organic anion transporter-B, MOAT-B	ENSG00000125257	Although reported to facilitate cellular cyclic nucleotide export, this role has been questioned (see Borst et al., 2007); reported to export prostaglandins in a manner sensitive to NSAIDS (Reid et al., 2003)
ABCC5	MRP5	Multidrug resistance-associated protein 5, multi-specific organic anion transporter-C, MOAT-C, pABC11, SMRP	ENSG00000114770	Although reported to facilitate cellular cyclic nucleotide export, this role has been questioned (see Borst et al., 2007)
ABCC6	MRP6	Multidrug resistance-associated protein 6, anthracycline resistance-associated protein, multi-specific organic anion transporter-E, MOAT-E	ENSG00000091262	–
ABCC7	CFTR	Cystic fibrosis transmembrane conductance regulator, cAMP-dependent chloride channel	ENSG00000001626	See page S214
ABCC10	MRP7	Multidrug resistance-associated protein 7	ENSG00000124574	–
ABCC11	MRP8	Multidrug resistance-associated protein 8	ENSG00000121270	Single nucleotide polymorphisms distinguish wet vs. dry earwax; association between earwax allele and breast cancer risk in Japanese but not European populations
ABCC12	MRP9	Multidrug resistance-associated protein 9	ENSG00000140798	–

ABCC8 (ENSG00000006071, also known as SUR1, sulfonylurea receptor 1) and ABCC9 (ENSG00000069431, also known as SUR2, sulfonylurea receptor 2) are unusual in that they lack transport capacity but regulate the activity of particular K⁺ channels (K_ir6.1-6.2, see Page S158), conferring nucleotide sensitivity to these channels to generate the canonical K_ATP channels. ABCC13 (ENSG00000155288) is a possible pseudogene.

ABCD subfamily of peroxisomal ABC transporters

This family of ‘half-transporters’ act as homo- or heterodimers to accumulate fatty acid-CoA esters into peroxisomes for oxidative metabolism (see Kemp et al., 2011).

Systematic name	Common abbreviation	Other names	Ensembl ID	Substrates
ABCD1	ALDP	Adrenoleukodystrophy protein	ENSG00000101986	Coenzyme A esters of very long chain fatty acids (van Roermund et al., 2008; 2011;)
ABCD2	ALDR	Adrenoleukodystrophy- related protein, adrenoleukodystrophy-like 1	ENSG00000173208	Coenzyme A esters of very long chain unsaturated fatty acids (van Roermund et al., 2011)
ABCD3	PMP70	70 kDa peroxisomal membrane protein, PXMP1	ENSG00000117528	–

ABCD4 (ENSG00000119688, also known as PMP69, PXMP1-L or P70R) appears to be located on the endoplasmic reticulum (Kashiwayama et al., 2009), with an unclear function. Loss-of-function mutations in the gene encoding ALDP underlie the metabolic storage disorder X-linked adrenoleukodystrophy.

ABCG subfamily

This family of ‘half-transporters’ act as homo- or heterodimers; particularly ABCG5 and ABCG8 are thought to be obligate heterodimers. They are associated with cellular export of sterols and phospholipids, as well as exogenous drugs (ABCG2).

Systematic name	Common abbreviation	Other names	Ensembl ID	Comments
ABCG1	ABC8	White protein homolog	ENSG00000160179	Transports sterols and choline phospholipids (see Kerr et al., 2011)
ABCG2	ABCP	Placenta-specific ATP- binding cassette transporter, breast cancer resistance protein, BCRP, mitoxantrone resistance-associated protein, MXR, CD338 antigen, CDw338	ENSG00000118777	Exhibits a broad substrate specificity, including urate and haem, as well as multiple synthetic compounds (see Kerr et al., 2011)
ABCG4	–	White2	ENSG00000172350	Putative functional dependence on ABCG1
ABCG5	–	White3, Sterolin-1	ENSG00000138075	Transports phytosterols; forms a heterodimer with ABCG8
ABCG8	–	Sterolin-2	ENSG00000143921	Transports phytosterols; forms a heterodimer with ABCG5

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 (Chen et al., 2006; Paytubi et al., 2009): ABCE1 (ENSG00000164163, also known as OABP or 2′-5′ oligoadenylate-binding protein); ABCF1 (ENSG00000204574, also known as ABC50 or TNF-α-stimulated ABC protein); ABCF2 (ENSG00000033050, also known as iron-inhibited ABC transporter 2) and ABCF3 (ENSG00000161204).

Abbreviations: ABC, ATP-binding cassette; NBD, nucleotide-binding domain; N-retinylPE, N-retinylphosphatidylethanolamine; NSAID, non-steroidal anti-inflammatory drugs

Further Reading

Aye IL, Singh AT, Keelan JA (2009). Transport of lipids by ABC proteins: interactions and implications for cellular toxicity, viability and function. Chem Biol Interact180: 327–339.

Borst P, de Wolf C, van de Wetering K (2007). Multidrug resistance-associated proteins 3, 4, and 5. Pflugers Arch453: 661–673.

Bryan J, Munoz A, Zhang X, Dufer M, Drews G, Krippeit-Drews P et al. (2007). ABCC8 and ABCC9: ABC transporters that regulate K+ channels. Pflugers Arch453: 703–718.

Ecker GF, Stockner T, Chiba P (2008). Computational models for prediction of interactions with ABC-transporters. Drug Discov Today13: 311–317.

Gutmann DA, Ward A, Urbatsch IL, Chang G, van Veen HW (2010). Understanding polyspecificity of multidrug ABC transporters: closing in on the gaps in ABCB1. Trends Biochem Sci35: 36–42.

Kemp S, Theodoulou FL, Wanders RJ (2011). Mammalian peroxisomal ABC transporters: from endogenous substrates to pathology and clinical significance. Br J Pharmacol in press.

Kerr ID, Haider AJ, Gelissen IC (2011). The ABCG family of membrane-associated transporters: you don't have to be big to be mighty. Br J Pharmacol in press.

Linton KJ, Higgins CF (2007). Structure and function of ABC transporters: the ATP switch provides flexible control. Pflugers Arch453: 555–567.

Miller DS (2010). Regulation of P-glycoprotein and other ABC drug transporters at the blood-brain barrier. Trends Pharmacol Sci31: 246–254.

Procko E, O'Mara ML, Bennett WF, Tieleman DP, Gaudet R (2009). The mechanism of ABC transporters: general lessons from structural and functional studies of an antigenic peptide transporter. FASEB J23: 1287–1302.

Ravna AW, Sager G (2009). Molecular modeling studies of ABC transporters involved in multidrug resistance. Mini Rev Med Chem9: 186–193.

Rees DC, Johnson E, Lewinson O (2009). ABC transporters: the power to change. Nat Rev Mol Cell Biol10: 218–227.

Russel FG, Koenderink JB, Masereeuw R (2008). Multidrug resistance protein 4 (MRP4/ABCC4): a versatile efflux transporter for drugs and signalling molecules. Trends Pharmacol Sci29: 200–207.

Schrickx JA, Fink-Gremmels J (2008). Implications of ABC transporters on the disposition of typical veterinary medicinal products. Eur J Pharmacol585: 510–519.

Seeger MA, van Veen HW (2009). Molecular basis of multidrug transport by ABC transporters. Biochim Biophys Acta1794: 725–737.

Sharom FJ (2008). ABC multidrug transporters: structure, function and role in chemoresistance. Pharmacogenomics9: 105–127.

Szakacs G, Varadi A, Ozvegy-Laczka C, Sarkadi B (2008). The role of ABC transporters in drug absorption, distribution, metabolism, excretion and toxicity (ADME-Tox). Drug Discov Today13: 379–393.

Wanders RJ, Visser WF, van Roermund CW, Kemp S, Waterham HR (2007). The peroxisomal ABC transporter family. Pflugers Arch453: 719–734.

F-type and V-type ATPases (EC 3.6.3.14)

The F-type (ATP synthase) and the V-type (vacuolar or vesicular proton pump) ATPases, although having distinct subcellular locations and roles, exhibit marked similarities in subunit structure and mechanism. They are both composed of a ‘soluble’ complex (termed F₁ or V₁) and a membrane complex (F_o or V_o). Within each ATPase complex, the two individual sectors appear to function as connected opposing rotary motors, coupling catalysis of ATP synthesis or hydrolysis to proton transport.

F-type ATPase

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 F_O channel domain in the membrane and an F₁ domain extending into the lumen. Proton transport across the inner mitochondrial membrane is used to drive the synthesis of ATP, although it is also possible for the enzyme to function as an ATPase. The ATP5O subunit (oligomycin sensitivity-conferring protein, OSCP, ENSG00000241837), which acts as a connector between F₁ and F₀ motors,

The F₁ motor, responsible for ATP turnover, has the subunit composition α3β3γδε.

Nomenclature	HGNC nomenclature	Ensembl ID	Other names
α	ATP5A1;	ENSG00000152234;	ATP5A, ATP5AL2, ATPM, hATP1, OMR, ORM;
	ATPAF2	ENSG00000171953	ATP synthase mitochondrial F1 complex assembly factor 2, ATP12, Atp12p
β	ATP5B;	ENSG00000110955;	ATPSB;
	ATPAF1	ENSG00000123472	ATP synthase mitochondrial F1 complex assembly factor 1, ATP11, Atp11p, FLJ22351
γ	ATP5C1	ENSG00000165629	ATP5C, ATP5CL1
δ	ATP5D	ENSG00000099624	–
ε	ATP5E	ENSG00000124172	–

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.

Nomenclature	HGNC nomenclature	Ensembl ID	Other names
A	MT-ATP6	ENSG00000198899	F-ATPase protein 6
B	ATP5F1	ENSG00000116459	–
C	ATP5G1;	ENSG00000159199;	ATP synthase proteolipid P1, ATPase protein 9
	ATP5G2;	ENSG00000135390;
	ATP5G3	ENSG00000154518
D	ATP5H	ENSG00000167863	ATP5JD, ATPQ
E	ATP5I	ENSG00000169020	ATP5K
F2	ATP5J2	ENSG00000241468	ATP5JL
F6	ATP5J	ENSG00000154723	ATP5, ATP5A, ATPM, CF6, ATP synthase-coupling factor 6
G2	ATP5L2	ENSG00000249222	ATP5K2
8	MT-ATP8	ENSG00000229604	–

Multiple pseudogenes for these proteins have been defined in the human genome.

V-type ATPase

The V-type ATPase is most prominently associated with lysosomes in mammals, but also appears to be expressed on the plasma membrane and neuronal synaptic vesicles.

The V₁ motor, responsible for ATP turnover, has eight subunits with a composition of A-H.

Nomenclature	HGNC nomenclature	Ensembl ID	Other names
A	ATP6V1A	ENSG00000114573	ATP6A1, ATP6V1A1, VA68, Vma1, VPP2
B1	ATP6V1B1	ENSG00000116039	ATP6B1, RTA1B, VATB, Vma2, VPP3
B2	ATP6V1B2	ENSG00000147416	ATP6B2, HO57, VATB, Vma2, VPP3
C1	ATP6V1C1	ENSG00000155097	ATP6C, ATP6D, VATC, Vma5
C2	ATP6V1C2	ENSG00000143882	ATP6C2, VMA5
D	ATP6V1D	ENSG00000100554	ATP6M, VATD, VMA8
E1	ATP61VE1	ENSG00000131100	ATP6E, ATP6E2, ATP6V1E, P31, Vma4
E2	ATP6V1E2	ENSG00000250565	ATP6E1, ATP6EL2, ATP6V1EL2, MGC9341, VMA4
F	ATP6V1F	ENSG00000128524	ATP6S14, VATF, Vma7
G1	ATP6V1G1	ENSG00000136888	ATP6G, ATP6G1, ATP6GL, ATP6J, DKFZp547P234, Vma10
G2	ATP6V1G2	ENSG00000230900;	ATP6G, ATP6G2, Em:AC004181.3, NG38, Vma10
		ENSG00000213760;
		ENSG00000234668;
		ENSG00000234920;
		ENSG00000206445;
		ENSG00000226850
G3	ATP6V1G3	ENSG00000151418	ATP6G3, Vma10
H	ATP6V1H	ENSG00000047249	CGI-11, SFD, SFDalpha, SFDbeta, VMA13

The V_o motor, responsible for ion translocation, has six subunits (a–e).

Nomenclature	HGNC nomenclature	Ensembl ID	Other names
a1	ATP6V0A1	ENSG00000033627	ATP6N1, ATP6N1A, Stv1, Vph1, VPP1
a2	ATP6V0A2	ENSG00000185344	ATP6a2, ATP6N1D, J6B7, Stv1, TJ6, TJ6M, TJ6s, Vph1
a3	TCIRG1	ENSG00000110719	T-cell immune regulator 1, Atp6i, ATP6N1C, ATP6V0A3, OC-116, OC116, TIRC7
a4	ATP6V0A4	ENSG00000105929	ATP6N1B, ATP6N2, RDRTA2, RTA1C, RTADR, Stv1, Vph1, VPP2
b	ATP6V0B	ENSG00000117410	ATP6F, HATPL, VMA16
c	ATP6V0C	ENSG00000185883	ATP6C, ATP6L, ATPL, VATL, Vma3
d1	ATP6V0D1	ENSG00000159720	ATP6D, ATP6DV, P39, VATX, Vma6, VPATPD
d2	ATP6V0D2	ENSG00000147614	ATP6D2, FLJ38708, VMA6
e1	ATP6V0E1	ENSG00000113732	ATP6H, ATP6V0E, M9.2
e2	ATP6V0E2	ENSG00000171130	ATP6V0E2L, C7orf32

Further Reading

von Ballmoos C (2007). Alternative proton binding mode in ATP synthases. J Bioenerg Biomembr39: 441–445.

von Ballmoos C, Cook GM, Dimroth P (2008). Unique rotary ATP synthase and its biological diversity. Annu Rev Biophys37: 43–64.

von Ballmoos C, Wiedenmann A, Dimroth P (2009). Essentials for ATP synthesis by F₁F₀ ATP synthases. Annu Rev Biochem78: 649–672.

Junge W, Sielaff H, Engelbrecht S (2009). Torque generation and elastic power transmission in the rotary F₀F₁-ATPase. Nature459: 364–370.

Nakamoto RK, Baylis Scanlon JA, Al-Shawi MK (2008). The rotary mechanism of the ATP synthase. Arch Biochem Biophys476: 43–50.

Nakanishi-Matsui M, Sekiya M, Nakamoto RK, Futai M (2010). The mechanism of rotating proton pumping ATPases. Biochim Biophys Acta1797: 1343–1352.

Navarro A, Boveris A (2007). The mitochondrial energy transduction system and the aging process. Am J Physiol Cell Physiol292: C670–C686.

Qi J, Wang Y, Forgac M (2007). The vacuolar (H⁺)-ATPase: subunit arrangement and in vivo regulation. J Bioenerg Biomembr39: 423–426.

P-type ATPases (EC 3.6.3.-)

Phosphorylation-type ATPases are associated with membranes and the transport of ions or phospholipids. A characteristic is the interconversion between E1 and E2 conformations in the activity cycle of the transporters.

Na⁺/K⁺-ATPase (EC 3.6.3.9)

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. The active enzyme is a heteromultimer with incompletely defined stoichiometry, possibly as tetramers of heterodimers, each consisting of one of four large, ten TM domain catalytic α subunits and one of three smaller single TM domain glycoprotein β-subunits (see table). Additional protein partners known as FXYD proteins (e.g. FXYD2, ENSG00000137731) appear to associate with and regulate the activity of the pump.

Nomenclature	Systematic name	Ensembl ID	Other names
α1	ATP1A1	ENSG00000163399	Sodium/potassium-transporting ATPase subunit α-1, sodium pump subunit α-1, Na+/K+ ATPase α-1 subunit
α2	ATP1A2	ENSG00000018625	Sodium/potassium-transporting ATPase subunit α-1, sodium pump subunit α-1, Na+/K+ ATPase α-1 subunit
α3	ATP1A3	ENSG00000105409	Sodium/potassium-transporting ATPase subunit α-3, sodium pump subunit α-3, Na+/K+ ATPase α-3 subunit
α4	ATP1A4	ENSG00000132681	Sodium/potassium-transporting ATPase subunit α-4, sodium pump subunit α-4, Na+/K+ ATPase α-4 subunit
β1	ATP1B1	ENSG00000143153	Sodium/potassium-transporting ATPase subunit β-1
β2	ATP1B2	ENSG00000129244	Sodium/potassium-transporting ATPase subunit β-2
β3	ATP1B3	ENSG00000069849	Sodium/potassium-transporting ATPase subunit β-3, CD298 antigen

Na⁺/K⁺-ATPases are inhibited by ouabain and cardiac glycosides, such as digoxin, as well as potentially endogenous cardiotonic steroids (see Bagrov et al., 2009).

Ca²⁺-ATPases (EC 3.6.3.8)

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.

Nomenclature	Systematic name	Ensembl ID	Other names
SERCA1	ATP2A1	ENSG00000196296	Sarcoplasmic/endoplasmic reticulum calcium ATPase 1, fast twitch skeletal muscle isoform
SERCA2	ATP2A2	ENSG00000174437	Sarcoplasmic/endoplasmic reticulum calcium ATPase 2, calcium pump 2, slow twitch skeletal muscle isoform
SERCA3	ATP2A3	ENSG00000074370	Sarcoplasmic/endoplasmic reticulum calcium ATPase 3

The fungal toxin ochratoxin A has been described to activate SERCA in kidney microsomes (Chong and Rahimtula, 1992). Cyclopiazonic acid (Seidler et al., 1989), thapsigargin (Lytton et al., 1991) and BHQ are widely employed to block SERCA. Thapsigargin has also been described to block the TRPV1 vanilloid receptor (Toth et al., 2002).

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.

Nomenclature	Systematic name	Ensembl ID	Other names
PMCA1	ATP2B1	ENSG00000070961	Plasma membrane calcium ATPase isoform 1
PMCA2	ATP2B2	ENSG00000157087	Plasma membrane calcium ATPase isoform 2
PMCA3	ATP2B3	ENSG00000067842	Plasma membrane calcium ATPase isoform 3
PMCA4	ATP2B4	ENSG00000058668	Plasma membrane calcium ATPase isoform 4, matrix-remodeling-associated protein 1

The stoichiometry of flux through the PMCA differs from SERCA, with the PMCA transporting 1 Ca²⁺ while SERCA transports 2 Ca²⁺.

Secretory pathway Ca²⁺-ATPases (SPCA) allow accumulation of calcium and manganese in the Golgi apparatus.

Nomenclature	Systematic name	Ensembl ID	Other names
SPCA1	ATP2C1	ENSG00000017260	ATPase 2C1, ATP-dependent Ca2+ pump PMR1
SPCA2	ATP2C2	ENSG00000064270	ATPase 2C2, secretory pathway Ca2+-ATPase 2

Loss-of-function mutations in SPCA1 appear to underlie Hailey-Hailey disease (Hu et al., 2000).

H⁺/K⁺-ATPase (EC 3.6.3.10)

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 (Pestov et al., 2006).

Nomenclature	Ensembl ID	Other names
ATP4A	ENSG00000105675	Potassium-transporting ATPase α chain 1, gastric H+/K+-ATPase α subunit, ATP6A
ATP12A	ENSG00000075673	Potassium-transporting ATPase α chain 2, non-gastric H+/K+-ATPase α subunit, ATP1AL1
ATP4B	ENSG00000186009	Potassium-transporting ATPase β chain 1, gastric H+/K+-ATPase β subunit

The gastric H⁺/K⁺-ATPase is inhibited by (r)-lansoprazole and a metabolite of (s)-omeprazole.

Cu²⁺-ATPase (EC 3.6.3.4)

Copper-transporting ATPases convey copper ions across cell-surface and intracellular membranes. They consist of eight TM domains and associate with multiple copper chaperone proteins (e.g. ATOX1, ENSG00000177556).

Nomenclature	Ensembl ID	Other names
ATP7A	ENSG00000165240	Copper-transporting ATPase 1, copper pump 1, Menkes disease-associated protein
ATP7B	ENSG00000123191	Copper-transporting ATPase 2, copper pump 2, Wilson disease-associated protein

Phospholipid-transporting ATPase (EC 3.6.3.1)

These transporters are thought to translocate the aminophospholipids phosphatidylserine and phosphatidylethanolamine from one side of the phospholipid bilayer to the other.

Nomenclature	Ensembl ID	Other names
ATP8A1	ENSG00000124406	Probable phospholipid-transporting ATPase IA, chromaffin granule ATPase II
ATP8A2	ENSG00000132932	Probable phospholipid-transporting ATPase IB, ML-1
ATP8B1	ENSG00000081923	Probable phospholipid-transporting ATPase IC, familial intrahepatic cholestasis type 1
ATP8B2	ENSG00000143515	Probable phospholipid-transporting ATPase ID
ATP8B3	ENSG00000130270	Probable phospholipid-transporting ATPase IK
ATP8B4	ENSG00000104043	Probable phospholipid-transporting ATPase IM
ATP9A	ENSG00000054793	Probable phospholipid-transporting ATPase IIA, ATPase IIA
ATP9B	ENSG00000166377	Probable phospholipid-transporting ATPase IIB, ATPase class II type 9B
ATP10A	ENSG00000206190	Probable phospholipid-transporting ATPase VA, ATPase class V type 10A, aminophospholipid translocase VA, ATP10C
ATP10B	ENSG00000118322	Probable phospholipid-transporting ATPase VB, ATPase class V type 10B
ATP10D	ENSG00000145246	Probable phospholipid-transporting ATPase VD, ATPase class V type 10D
ATP11A	ENSG00000068650	Probable phospholipid-transporting ATPase IH, ATPase class VI type 11A, ATPase IS
ATP11B	ENSG00000058063	Probable phospholipid-transporting ATPase IF, ATPase class VI type 11B, ATPase IR
ATP11C	ENSG00000101974	Probable phospholipid-transporting ATPase IG, ATPase class VI type 11C, ATPase IG, ATPase IQ

Loss-of-function mutations in ATP8B1 are associated with type I familial intrahepatic cholestasis.

A further series of structurally-related proteins have been identified in the human genome, with as yet undefined function, including ATP13A1 (ENSG00000105726), ATP13A2 (ENSG00000159363), ATP13A3 (ENSG00000133657), ATP13A4 (ENSG00000127249) and ATP13A5 (ENSG00000187527).

Abbreviations: BHQ, 2,5-di-t-butyl-1,4 benzohydroquinone

Further Reading

Bagrov AY, Shapiro JI, Fedorova OV (2009). Endogenous cardiotonic steroids: physiology, pharmacology, and novel therapeutic targets. Pharmacol Rev61: 9–38.

Benarroch EE (2011). Na⁺, K⁺-ATPase: functions in the nervous system and involvement in neurologic disease. Neurology76: 287–293.

Bers DM, Despa S (2009). Na/K-ATPase – an integral player in the adrenergic fight-or-flight response. Trends Cardiovasc Med19: 111–118.

Brini M (2009). Plasma membrane Ca²⁺-ATPase: from a housekeeping function to a versatile signaling role. Pflugers Arch457: 657–664.

Brini M, Carafoli E (2009). Calcium pumps in health and disease. Physiol Rev89: 1341–1378.

Cartwright EJ, Oceandy D, Neyses L (2009). Physiological implications of the interaction between the plasma membrane calcium pump and nNOS. Pflugers Arch457: 665–671.

Di Leva F, Domi T, Fedrizzi L, Lim D, Carafoli E (2008). The plasma membrane Ca²⁺ ATPase of animal cells: structure, function and regulation. Arch Biochem Biophys476: 65–74.

Fedorova OV, Shapiro JI, Bagrov AY (2010). Endogenous cardiotonic steroids and salt-sensitive hypertension. Biochim Biophys Acta1802: 1230–1236.

Floyd R, Wray S (2007). Calcium transporters and signalling in smooth muscles. Cell Calcium42: 467–476.

Folmer DE, Elferink RP, Paulusma CC (2009). P4 ATPases – lipid flippases and their role in disease. Biochim Biophys Acta1791: 628–635.

Inesi G, Prasad AM, Pilankatta R (2008). The Ca²⁺ ATPase of cardiac sarcoplasmic reticulum: physiological role and relevance to diseases. Biochem Biophys Res Commun369: 182–187.

Jaitovich A, Bertorello AM (2010). Salt, Na⁺, K⁺-ATPase and hypertension. Life Sci86: 73–78.

Kaler SG (2011). ATP7A-related copper transport diseases-emerging concepts and future trends. Nat Rev Neurol7: 15–29.

Kawase Y, Hajjar RJ (2008). The cardiac sarcoplasmic/endoplasmic reticulum calcium ATPase: a potent target for cardiovascular diseases. Nat Clin Pract Cardiovasc Med5: 554–565.

Lingrel JB (2010). The physiological significance of the cardiotonic steroid/ouabain-binding site of the Na,K-ATPase. Annu Rev Physiol72: 395–412.

Manunta P, Messaggio E, Casamassima N, Gatti G, Carpini SD, Zagato L et al. (2010). Endogenous ouabain in renal Na⁺ handling and related diseases. Biochim Biophys Acta1802: 1214–1218.

Morth JP, Pedersen BP, Buch-Pedersen MJ, Andersen JP, Vilsen B, Palmgren MG et al. (2011). A structural overview of the plasma membrane Na⁺,K⁺-ATPase and H⁺-ATPase ion pumps. Nat Rev Mol Cell Biol12: 60–70.

Muthusamy BP, Natarajan P, Zhou X, Graham TR (2009). Linking phospholipid flippases to vesicle-mediated protein transport. Biochim Biophys Acta1791: 612–619.

Patel S, Docampo R (2010). Acidic calcium stores open for business: expanding the potential for intracellular Ca2+ signaling. Trends Cell Biol20: 277–286.

Poulsen H, Morth P, Egebjerg J, Nissen P (2010). Phosphorylation of the Na⁺,K⁺-ATPase and the H⁺,K⁺-ATPase. FEBS Lett584: 2589–2595.

Prassas I, Diamandis EP (2008). Novel therapeutic applications of cardiac glycosides. Nat Rev Drug Discov7: 926–935.

Puts CF, Holthuis JC (2009). Mechanism and significance of P4 ATPase-catalyzed lipid transport: lessons from a Na⁺/K⁺-pump. Biochim Biophys Acta1791: 603–611.

Rasmussen HH, Hamilton EJ, Liu CC, Figtree GA (2010). Reversible oxidative modification: implications for cardiovascular physiology and pathophysiology. Trends Cardiovasc Med20: 85–90.

Rosenberg PB (2009). Calcium entry in skeletal muscle. J Physiol587: 3149–3151.

Scarpignato C, Hunt RH (2008). Proton pump inhibitors: the beginning of the end or the end of the beginning? Curr Opin Pharmacol8: 677–684.

Tadini-Buoninsegni F, Bartolommei G, Moncelli MR, Fendler K (2008). Charge transfer in P-type ATPases investigated on planar membranes. Arch Biochem Biophys476: 75–86.

Taub M, Springate JE, Cutuli F (2010). Targeting of renal proximal tubule Na,K-ATPase by salt-inducible kinase. Biochem Biophys Res Commun393: 339–344.

Toyoshima C (2009). How Ca²⁺-ATPase pumps ions across the sarcoplasmic reticulum membrane. Biochim Biophys Acta1793: 941–946.

Weidemuller C, Hauser K (2009). Ion transport and energy transduction of P-type ATPases: implications from electrostatic calculations. Biochim Biophys Acta1787: 721–729.

Wray S, Burdyga T (2010). Sarcoplasmic reticulum function in smooth muscle. Physiol Rev90: 113–178.

Zhang L, Zhang Z, Guo H, Wang Y (2008). Na⁺/K⁺-ATPase-mediated signal transduction and Na⁺/K⁺-ATPase regulation. Fundam Clin Pharmacol22: 615–621.

The SLC superfamily of solute carriers

The SLC superfamily of solute carriers is the second largest family of membrane proteins after G protein-coupled receptors, but with a great deal fewer therapeutic drugs that exploit them. As with the ABC transporters, however, they play a major role in drug disposition and so can be hugely influential in determining the clinical efficacy of particular drugs.

48 families are identified on the basis of sequence similarities, but many of them overlap in terms of the solutes that they carry. For example, amino acid accumulation is mediated by members of the SLC1, SLC3/7, SLC6, SLC15, SLC16, SLC17, SLC32, SLC36, SLC38 and SLC43. Further members of the SLC superfamily regulate ion fluxes at the plasma membrane, or solute transport into and out of cellular organelles.

Within the SLC superfamily, there is an abundance in diversity of structure. Two families (SLC3 and SLC7) only generate functional transporters as heteromeric partners, where one partner is a single TM domain protein. Membrane topology predictions for other families suggest 3, 4 6, 7, 8, 9, 10, 11, 12, 13, or 14 TM domains. Functionally, members may be divided into those dependent on gradients of ions (particularly sodium, chloride or protons), exchange of solutes or simple equilibrative gating. For many members, the stoichiometry of transport is not yet established. Furthermore, one family of transporters also possess enzymatic activity (SLC27), while many members function as ion channels (e.g. SLC1A7/EAAT5), which increases the complexity of function of the SLC superfamily.

Further Reading

Fredriksson R, Nordstrom KJ, Stephansson O, Hagglund MG, Schioth HB (2008). The solute carrier (SLC) complement of the human genome: phylogenetic classification reveals four major families. FEBS Lett582: 3811–3816.

Giacomini KM, Huang SM, Tweedie DJ, Benet LZ, Brouwer KL, Chu X et al. (2010). Membrane transporters in drug development. Nat Rev Drug Discovery9: 215–236.

SLC1 family of amino acid transporters

Overview: The SLC1 family of sodium dependent transporters includes the plasma membrane located glutamate transporters and the neutral amino acid transporters ASCT1 and ASCT2 (Amara and Arriza, 1993; Palacín et al., 1998; Kanai and Hediger, 2003; 2004; Beart and O'Shea, 2007).

Glutamate transporter subfamily

Glutamate transporters present the unusual structural motif of 8TM segments and 2 re-entrant loops (Grunwald and Kanner, 2000). The crystal structure of a glutamate transporter homologue (Glt_Ph) 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 (Yernool et al., 2004; Boudker et al., 2007; Reyes et al., 2009; reviewed by Jiang and Amara, 2011). These structural data are in agreement with the proposed quaternary structure for EAAT2 (Gendreau et al., 2004) and several functional studies that propose the monomer is the functional unit (Ryan et al., 2004; Grewer et al., 2005; Koch et al., 2007; Leary et al., 2007). Recent evidence suggests that EAAT3 and EAAT4 may assemble as heterotrimers (Nothmann et al., 2011). The activity of glutamate transporters located upon both neurones (predominantly EAAT3, 4 and 5) and glia (predominantly EAAT 1 and 2) serves, dependent upon their location, to regulate excitatory neurotransmission, maintain low ambient extracellular concentrations of glutamate (protecting against excitotoxicity) and provide glutamate for metabolism including the glutamate-glutamine cycle. The Na⁺/K⁺-ATPase (see Page S219) that maintains the ion gradients that drive transport has been demonstrated to co-assemble with EAAT1 and EAAT2 (Rose et al., 2009). Recent evidence supports altered glutamate transport and novel roles in brain for splice variants of EAAT1 and EAAT2 (Gebhardt et al., 2010; Lee and Pow, 2010). Three patients with dicarboxylic aminoaciduria (DA) were recently found to have loss-of-function mutations in EAAT3 (Bailey et al., 2011). DA is characterized by excessive excretion of the acidic amino acids glutamate and aspartate and EAAT3 is the predominant glutamate/aspartate transporter in the kidney. Enhanced expression of EAAT2 resulting from administration of ß-lactam antibiotics (e.g. ceftriaxone) is neuroprotective and occurs through NF-κB-mediated EAAT2 promoter activation (Rothstein et al., 2005; Ganel et al., 2006; Lee et al., 2008; reviewed by Kim et al., 2010). PPARγ (see Page S181) activation (e.g. by rosiglitazone) also leads to enhanced expression of EAAT though promoter activation (Romera et al., 2007). In addition, several translational activators of EAAT2 have recently been described (Colton et al., 2010) along with treatments that increase the surface expression of EAAT2 (e.g.Lau et al., 2011, Zou et al., 2011), or prevent its down-regulation (e.g.Goursaud et al., 2011). A thermodynamically uncoupled Cl^- flux, activated by Na⁺ and glutamate (Kanai and Hediger, 2003; Grewer and Rauen, 2005; Machtens et al., 2011) (Na⁺ and aspartate in the case of Glt_Ph, Ryan and Mindell, 2007), is sufficiently large, in the instances of EAAT4 and EAAT5, to influence neuronal excitability (Veruki et al., 2006; Torres-Salazar and Fahlke, 2007). 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 (Gameiro et al., 2011).

Common abbreviation	EAAT1	EAAT2	EAAT3
Systematic name	SLC1A3	SLC1A2	SCL1A1
Nomenclature	Excitatory amino acid transporter 1	Excitatory amino acid transporter 2	Excitatory amino acid transporter 3
Other names	GLAST	GLT1	EAAC1
Ensembl ID	ENSG000000079215	ENSG00000110436	ENSG00000106688
Endogenous substrates	L-glutamate, L-aspartate	L-glutamate, L-aspartate	L-glutamate, L-aspartate, L-cysteine (Zerangue and Kavanaugh, 1996a)
Synthetic substrates	DL-threo-β-hydroxyaspartate, L-trans-2,4-pyrolidine dicarboxylate	DL-threo-β-hydroxyaspartate, L-trans-2,4-pyrolidine dicarboxylate	DL-threo-β-hydroxyaspartate, L-trans-2,4-pyrolidine dicarboxylate
Inhibitors (KBor Ki)	UCPH-101 (IC50 = 120 nM – membrane potential assay, Jensen et al., 2009), DL-TBOA (9 µM)	WAY-213613 (IC50 = 130 nM), DL-TBOA (0.12 µM), (2S,4R)-4-methylglutamate (3.4 µM), dihydrokainate (9 µM), Threo-3-methylglutamate (18 µM)	NBI-59159 (IC50 = 25 nM), DL-TBOA (IC50 = 8 µM), L-β-BA (IC50 = 0.8 µM –[3H]-D-aspartate uptake assay)
Probes	[3H]-ETB-TBOA (KD = 15.5 nM), [3H]-[(2S,4R)-4-methylglutamate, [3H]-D-aspartate, [3H]-L-aspartate	[3H]-ETB-TBOA (KD = 16.2 nM), [3H]-[(2S,4R)-4-methylglutamate, [3H]-D-aspartate, [3H]-L-aspartate	[3H]-ETB-TBOA (KD = 320 nM), [3H]-D-aspartate, [3H]-L-aspartate
Stoichiometry	Probably 3 Na+: 1 H+: 1 glutamate (in): 1 K+ (out)	3 Na+: 1 H+: 1 glutamate (in): 1 K+ (out) (Levy et al., 1998)	3 Na+: 1 H+: 1 glutamate (in): 1 K+ (out) (Zerangue and Kavanaugh, 1996b)

Common abbreviation	EAAT4	EAAT5
Systematic name	SLC1A6	SLC1A7
Nomenclature	Excitatory amino acid transporter 4	Excitatory amino acid transporter 5
Ensembl ID	ENSG00000105143	ENSG00000162383
Endogenous substrates	L-glutamate, L-aspartate	L-glutamate, L-aspartate
Synthetic substrates	DL-threo-β-hydroxyaspartate, L-trans-2,4-pyrolidine dicarboxylate	DL-threo-β-hydroxyaspartate, L-trans-2,4-pyrolidine dicarboxylate
Inhibitors (KB or Ki)	DL-TBOA (4.4 µM), Threo-3-methylglutamate (50 µM)	DL-TBOA (3.2 µM)
Probes	[3H]-ETB-TBOA (KD = 24.8 nM), [3H]-D-aspartate, [3H]-L-aspartate	[3H]-ETB-TBOA (KD = 29.5 nM), [3H]-D-aspartate, [3H]-L-aspartate
Stoichiometry	Probably 3 Na+: 1 H+: 1 glutamate (in): 1 K+ (out)	Probably 3 Na+: 1 H+: 1 glutamate (in): 1 K+ (out)

The K_B (or K_i) values reported, unless indicated otherwise, are derived from transporter currents mediated by EAATs expressed in voltage-clamped Xenopus laevis oocytes (Vandenberg et al., 1997; Shimamoto et al., 1998; Eliasof et al. 2001; Shigeri et al. 2001). K_B (or K_i) values derived in uptake assays are generally higher (e.g.Shimamoto et al., 1998). In addition to acting as a poorly transportable inhibitor of EAAT2, (2S,4R)-4-methylglutamate, also known as SYM2081, is a competitive substrate for EAAT1 (K_M = 54 µM; Vandenberg et al., 1997; Huang et al., 2009) and additionally is a potent kainate receptor agonist (Zhou et al., 1997) which renders the compound unsuitable for autoradiographic localisation of EAATs (Apricòet al., 2007). Similarly, at concentrations that inhibit EAAT2, dihydrokainate binds to kainate receptors (Shimamoto et al. 1998). WAY-855 and WAY-213613 are both non-substrate inhibitors with a preference for EAAT2 over EAAT3 and EAAT1 (Dunlop et al., 2003; Dunlop et al., 2005). NBI-59159 is a non-substrate inhibitor with modest selectivity for EAAT3 over EAAT1 (>10-fold) and EAAT2 (5-fold) (Coon et al., 2004; Dunlop, 2006). Analogously, L-β-threo-benzyl-aspartate (L-β-BA) is a competitive non-substrate inhibitor that preferentially blocks EAAT3 versus EAAT1, or EAAT2 (Esslinger et al., 2005b). [³H]-[(2S,4R)-4-methylglutamate demonstrates low affinity binding (K_D≅ 6.0 µM) to EAAT1 and EAAT2 in rat brain homogenates (Apricóet al., 2001) and EAAT1 in murine astrocyte membranes (Apricòet al., 2004), whereas [³H]-ETB-TBOA binds with high affinity to all EAATs other than EAAT3 (Shimamoto et al., 2007). The novel isoxazole derivative (-)-HIP-A may interact at the same site as TBOA and preferentially inhibit reverse transport of glutamate (Colleoni et al., 2008). Threo-3-methylglutamate induces substrate-like currents at EAAT4, but does not elicit heteroexchange of [³H]-aspartate in synaptosome preparations, inconsistent with the behaviour of a substrate inhibitor (Eliasof et al., 2001). Parawixin1, 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 (Fontana et al., 2003, 2007). In addition to the agents listed in the table, DL-threo-β-hydroxyaspartate and L-trans-2,4-pyrolidine dicarboxylate act as non-selective competitive substrate inhibitors of all EAATs. Zn²⁺ and arachidonic acid are putative endogenous modulators of EAATs with actions that differ across transporter subtypes (reviewed by Vandenberg et al., 2004).

Alanine/serine/cysteine transporter subfamily

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 (Arizza et al., 1993; Utsunomiya-Tate et al., 1996). ASCT1 and ASCT2 also exhibit thermodynamically uncoupled chloride channel activity associated with substrate transport (Zerangue and Kavanaugh, 1996c; Bröer et al., 2000). Whereas EAATs counter-transport K⁺ (see above) ASCTs do not and their function is independent of the intracellular concentration of K⁺ (Zerangue and Kavanaugh, 1996c).

Common abbreviation	ASCT1	ASCT2
Systematic name	SLC1A4	SLC1A5
Nomenclature	Alanine/serine/cysteine transporter 1	Alanine/serine/cysteine transporter 2
Other names	Neutral amino acid transporter A, SATT	Neutral amino acid transporter B(0), hATB0, AAAT
Ensembl ID	ENSG00000115902	ENSG00000105281
Endogenous substrates	L-cysteine > L-alanine = L-serine > L-threonine	L-alanine = L-serine = L-cysteine (low Vmax) = L-threonine = L-glutamine = L-asparaginine >> L-methionine ≅ L-glycine ≅ L-leucine > L-valine > L-glutamate (enhanced at low pH)
Inhibitors	–	p-nitrophenyl glutamyl anilide (Esslinger et al., 2005a), benzylserine, benzylcysteine (Grewer and Grabsch, 2004)
Predicted stoichiometry	1 Na+: 1 amino acid (in): 1 Na+: 1 amino acid (out); (homo-, or hetero-exchange; Zerangue and Kavanaugh, 1996b)	1 Na+: 1 amino acid (in): 1 Na+: 1 amino acid (out); (homo-, or hetero-exchange; Bröer et al., 1999)

The substrate specificity of ASCT1 may extend to proline and hydroxyproline (Pinilla-Tenas et al., 2003). At low pH (∼5.5) both ASCT1 and ASCT2 are able to exchange acidic amino acids such as cysteate and glutamate (Tamarappoo et al., 1996; Utsunomiya-Tate et al., 1996). In addition to the inhibitors tabulated above, HgCl₂, methymercury, mersalyl, at low micromolar concentrations, non-competitively inhibit ASCT2 by covalent modification of cysteine residues (Oppedisano et al., 2010).

Further Reading

Beart PM, O'Shea RD (2007). Transporters for L-glutamate: an update on their molecular pharmacology and pathological involvement. Br J Pharmacol150: 5–17.

Bridges RJ, Esslinger CS (2005). The excitatory amino acid transporters: pharmacological insights on substrate and inhibitor specificity of the EAAT subtypes. Pharmacol Ther107: 271–285.

Bunch L, Erichsen MN, Jensen AA (2009). Excitatory amino acid transporters as potential drug targets. Expert Opin Ther Targets13: 719–731.

Chao XD, Fei F, Fei Z (2010).The role of excitatory amino acid transporters in cerebral ischemia. Neurochem Res35: 1224–1230.

Danbolt NC (2001). Glutamate uptake. Prog Neurobiol65: 1–105.

Dunlop J (2006). Glutamate based therapeutic approaches: targeting the glutamate transport system. Curr Opin Pharmacol6: 103–107.

Dunlop J, Butera JA (2006). Ligands targeting the excitatory amino acid transporters (EAATs). Curr Top Med Chem6: 1897–1906.

Fuchs BC, Bode BP (2005). Amino acid transporters ASCT2 and LAT1 in cancer: partners in crime? Semin Cancer Biol15: 254–266.

Grewer C, Rauen T (2005). Electrogenic glutamate transporters in the CNS: molecular mechanism, pre-steady-state kinetics, and their impact on synaptic signaling. J Membr Biol203: 1–20.

Grewer C, Gameiro A, Zhang Z, Tao Z, Braams S, Rauen T (2008). Glutamate forward and reverse transport: from molecular mechanism to transporter-mediated release after ischemia. IUBMB Life60: 609–619.

Hinoi E, Takarada T, Tsuchihashi Y, Yoneda Y (2005). Glutamate transporters as drug targets. Curr Drug Targets CNS Neurol Disord4: 211–220.

Huang YH, Bergles DE (2004). Glutamate transporters bring competition to the synapse. Cur Opin Neurobiol14: 346–352.

Kanai Y, Hediger MA (2003). The glutamate and neutral amino acid transporter family: physiological and pharmacological implications. Eur J Pharmacol479: 237–247.

Kanai Y, Hediger MA (2004). The glutamate/neutral amino acid transporter family SLC1: molecular, physiological and pharmacological aspects. Pflügers Archiv447: 465–468.

Jiang J, Amara SG (2011). New views of glutamate transporter structure and function: advances and challenges. Neuropharmacology60: 172–181.

Kanner BI (2006). Structure and function of sodium-coupled GABA and glutamate transporters. J Membr Biol213: 89–100.

Kanner BI, Zomot E (2008). Sodium-coupled neurotransmitter transporters. Chem Rev108:1654–1668.

Kim K, Lee SG, Kegelman TP, Su ZZ, Das SK, Dash R et al. (2010). Role of excitatory amino acid transporter-2 (EAAT2) and glutamate in neurodegeneration: opportunities for developing novel therapeutics. J Cell Physiol226: 2484–2493.

Lee A, Pow DV (2010). Astrocytes: glutamate transport and alternate splicing of transporters. Int J Biochem Cell Biol42: 1901–1906.

McGivan JD, Bungard CI (2007). The transport of glutamine into mammalian cells. Front Biosci12: 874–882.

Palacín M, Estévez R, Bertran J, Zorano A (1998). Molecular biology of mammalian plasma membrane amino acid transporters Physiol Rev78: 969–1054.

Ryan RM, Vandenberg RJ (2005). A channel in a transporter. Clin Exp Pharmacol Physiol32: 1–6.

Sheldon AL, Robinson MB (2007). The role of glutamate transporters in neurodegenerative diseases and potential opportunities for intervention. Neurochem Int51: 333–355.

Shigeri Y, Seal RP, Shimamoto K (2004). Molecular pharmacology of glutamate transporters, EAATs and VGLUTs. Brain Res Brain Res Rev45: 250–265.

Shimamoto K (2008). Glutamate transporter blockers for elucidation of the function of excitatory neurotransmission systems. Chem Rec8: 182–199.

Sonders MS, Quick M, Javitch JA (2005). How did the neurotransmitter cross the bilayer? A closer look. Curr Opin Neurobiol15: 296–304.

Tzingouris AV, Wadiche JI (2007). Glutamate transporters: confining runaway excitation by shaping synaptic transmission. Nat Rev Neurosci8: 935–947.

Vandenberg RJ (2006). Mutational analysis of glutamate transporters. Handb Exp Pharmacol175:113–135.

Vandenberg RJ, Ryan RM (2005). How and why are channels in transporters? Sci STKE19: pe17.

Vandenberg RJ, Ju P, Aubrey KR, Ryan RM, Mitrovic AD (2004). Allosteric modulation of neurotransmitter transporters at excitatory synapses. Eur J Pharm Sci23: 1–11.

Vandenberg RJ, Huang S, Ryan RM (2008). Slips, leaks and channels in glutamate transporters. Channels (Austin)2: 51–58.

SLC2 family of hexose and sugar alcohol transporters

Overview: the SLC2 family transports glucose, fructose, inositol and related hexoses. Three classes of glucose transporter can be identified, separating GLUT1-4 and 14; GLUT6, 8, 10 and 12; and GLUT5, 7, 9 and 11. Modelling suggests a 12 TM membrane topology, with intracellular termini, with functional transporters acting as homodimers or homotetramers.

Class I transporters are able to transport glucose, but not fructose, in the direction of the concentration gradient and may be inhibited non-selectively by phloretin and cytochalasin B. GLUT1 is the major glucose transporter in brain, placenta and erythrocytes, GLUT2 is found in the pancreas, liver and kidneys, GLUT3 is neuronal and placental, while GLUT4 is the insulin-responsive transporter found in skeletal muscle, heart and adipose tissue. GLUT14 appears to result from gene duplication of GLUT3 and is expressed in the testes (Wu and Freeze, 2002).

Systematic name	SLC2A1	SLC2A2	SLC2A3	SLC2A4	SLC2A14
Preferred abbreviation	GLUT1	GLUT2	GLUT3	GLUT4	GLUT14
Nomenclature	Glucose transporter 1	Glucose transporter 2	Glucose transporter 3	Glucose transporter 4	Glucose transporter 14
Other names	HepG2 glucose transporter, erythrocyte/brain glucose transporter	Liver glucose transporter	Fructose transporter, brain glucose transporter	Insulin-responsive glucose transporter	–
Ensembl ID	ENSG00000117394	ENSG00000163581	ENSG00000059804	ENSG00000181856	ENSG00000173262
Substrates	Glucose = glucosamine (Uldry et al., 2002), dehydroascorbic acid (Bianchi and Rose, 1986)	Glucosamine > glucose (Uldry et al., 2002)	Glucose	Glucosamine > glucose (Uldry et al., 2002)	–
Probes	[3H]-2-Deoxyglucose	[3H]-2-Deoxyglucose	[3H]-2-Deoxyglucose	[3H]-2-Deoxyglucose	–

Class II transporters transport fructose and appear to be insensitive to cytochalasin B.

Systematic name	SLC2A5	SLC2A7	SLC2A9	SLC2A11
Preferred abbreviation	GLUT5	GLUT7	GLUT9	GLUT11
Nomenclature	Glucose transporter 5	Glucose transporter 7	Glucose transporter 9	Glucose transporter 11
Other names	Small intestine glucose transporter	–	–	–
Ensembl ID	ENSG00000142583	ENSG00000197241	ENSG00000109667	ENSG00000133460
Substrates	Fructose > glucose (Burant et al., 1992)	Fructose, glucose (Cheeseman, 2008)	Fructose, uric acid (Caulfield et al., 2008)	Glucose (Doege et al., 2001), fructose (Manolescu et al., 2007)

Class II transporters appear to be predominantly intracellularly located.

Systematic name	SLC2A6	SLC2A8	SLC2A10	SLC2A12
Preferred abbreviation	GLUT6	GLUT8	GLUT10	GLUT12
Nomenclature	Glucose transporter 6	Glucose transporter 8	Glucose transporter 10	Glucose transporter 12
Ensembl ID	ENSG00000160326	ENSG00000136856	ENSG00000197496	ENSG00000146411
Substrates	–	Glucose (Ibberson et al., 2000)	Glucose, dehydroascorbic acid (Lee et al., 2010)	Glucose (Rogers et al., 2003)

Proton-coupled inositol transporters are expressed predominantly in the brain and can be inhibited by phloretin and cytochalasin B (Uldry et al., 2002).

Systematic name	SLC2A13
Preferred abbreviation	HMIT
Nomenclature	Proton myo-inositol cotransporter
Ensembl ID	ENSG00000151229
Other names	H+-myo-inositol symporter
Substrates	myo-Inositol, scyllo-inositol, chiro-inositol, muco-inositol (Uldry et al., 2002)
Stoichiometry	1 H+: 1 inositol (in) (Di Daniel et al., 2009)

Further Reading

Augustin R (2010). The protein family of glucose transport facilitators: it's not only about glucose after all. IUBMB Life62: 315–333.

Leney SE, Tavare JM (2009). The molecular basis of insulin-stimulated glucose uptake: signalling, trafficking and potential drug targets. J Endocrinol203: 1–18.

Uldry M, Thorens B (2004). The SLC2 family of facilitated hexose and polyol transporters. Pflugers Arch447: 480–489.

SLC3 and SLC7 families of heteromeric amino acid transporters (HATs)

Overview: these families combine to generate functional transporters, where the subunit composition is a disulphide-linked combination of a heavy chain (SLC3 family) with a light chain (SLC7 family).

SLC3 family 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.

Systematic name	SLC3A1	SLC3A2
Common abbreviation	RBAT	4F2hc
Nomenclature	Cystine, dibasic, and neutral amino acid transporter	4F2 cell-surface antigen heavy chain
Ensembl ID	ENSG00000138079	ENSG00000168003
Other names	B0,+-type amino acid transport protein; D2H, ATR1	CD98 antigen Lymphocyte activation antigen 4F2 large subunit

SLC7 family members may be divided into two major groups: cationic amino acid transporters (CATs) and glycoprotein-associated amino acid transporters (gpaATs).

Cationic amino acid transporters are 14 TM proteins, which mediate pH- and sodium-independent transport of cationic amino acids (system y⁺), apparently as an exchange mechanism. These transporters are sensitive to inhibition by N-ethylmaleimide.

Systematic name	SLC7A1	SLC7A2	SLC7A3	SLC7A4	SLC7A14
Preferred abbreviation	CAT1	CAT2	CAT3	CAT4	–
Nomenclature	High affinity cationic amino acid transporter 1	Low affinity cationic amino acid transporter 2	Cationic amino acid transporter 3	Cationic amino acid transporter 4	–
Ensembl ID	ENSG00000139514	ENSG00000003989	ENSG00000165349	ENSG00000099960	ENSG00000013293
Other names	System Y+ basic amino acid transporter, ecotropic retroviral leukemia receptor homolog, ERR, ATRC1	ATRC2	Cationic amino acid transporter y+	–	–
Substrates	L-Arginine, L-lysine, L-ornithine, L-histidine	L-Arginine, L-lysine, L-ornithine, L-histidine	L-Arginine, L-lysine, L-ornithine	–	–

CAT4 appears to be non-functional in heterologous expression (Wolf et al., 2002), 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 hLAT1 or hLAT2 generate sodium-independent system L transporters. These transport large neutral amino acids (L-leucine, L-isoleucine and L-methionine).

Heterodimers between 4F2hc and y+LAT1 or y+LAT2 generate sodium-dependent transporters, similar to the system y⁺L transporters. These transporters are N-ethylmaleimide-insensitive and transport neutral (L-leucine) as well as cationic (L-arginine, L-lysine and L-ornithine) amino acids. Heterodimers between RBAT and B^0,+AT appear to mediate sodium-independent system b^0,+ transport of neutral and cationic amino acids (L-leucine, L-arginine, L-lysine and L-ornithine).

Systematic name	SLC7A5	SLC7A8	SLC7A7	SLC7A6	SLC7A9
Preferred abbreviation	hLAT1	hLAT2	y+LAT1	y+LAT2	B0,+AT
Nomenclature	L-type amino acid transporter 1	L-type amino acid transporter 2	y+L amino acid transporter 1	y+L amino acid transporter 2	B0,+-type amino acid transporter 1
Ensembl ID	ENSG00000103257	ENSG00000092068	ENSG00000155465	ENSG00000103064	ENSG00000021488
Other names	Large neutral amino acids transporter small subunit 1, y+ system cationic amino acid transporter, 4F2 light chain, 4F2LC, CD98 light chain, integral membrane protein E16	Large neutral amino acids transporter small subunit 2	Monocyte amino acid permease 2, MOP-2	Cationic amino acid transporter, y+ system	Glycoprotein-associated amino acid transporter

Asc-1 appears to heterodimerize with 4F2hc to allow the transport of small neutral amino acids (such as L-alanine, L-serine and glycine), as well as D-serine, in a sodium-independent manner.

xCT generates a heterodimer with 4F2hc for a system x^-_c transporter that accumulates cystine in a sodium-independent manner.

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.

Systematic name	SLC7A10	SLC7A11	SLC7A13
Preferred abbreviation	Asc-1	xCT	XAT2
Nomenclature	Asc-type amino acid transporter 1	–	AGT1
Ensembl ID	ENSG00000130876	ENSG00000151012	ENSG00000164893

Abbreviations: CAT, cationic amino acid transporter, gpaAT, glycoprotein-associated amino acid transporter

Further Reading

Closs EI, Boissel JP, Habermeier A, Rotmann A (2006). Structure and function of cationic amino acid transporters (CATs). J Membr Biol213: 67–77.

Palacin M, Kanai Y (2004). The ancillary proteins of HATs: SLC3 family of amino acid transporters. Pflugers Arch447: 490–494.

Palacin M, Nunes V, Font-Llitjos M, Jimenez-Vidal M, Fort J, Gasol E et al. (2005). The genetics of heteromeric amino acid transporters. Physiology (Bethesda)20: 112–124.

Verrey F, Closs EI, Wagner CA, Palacin M, Endou H, Kanai Y (2004). CATs and HATs: the SLC7 family of amino acid transporters. Pflugers Arch447: 532–542.

SLC4 family of bicarbonate transporters

Overview: together with the SLC26 family, the SLC4 family of transporters subserve anion exchange, principally of chloride and bicarbonate, but also carbonate and hydrogen sulphate (HSO₄^-). SLC4 family members regulate bicarbonate fluxes as part of carbon dioxide movement, chyme neutralization and reabsorption in the kidney.

Within the family, subgroups of transporters are identifiable: the electroneutral sodium-independent Cl^-/HCO₃^- transporters (AE1, AE2 and AE3), the electrogenic sodium-dependent HCO₃^- transporters (NBCe1 and NBCe2) and the electroneutral HCO₃^- transporters (NBCn1 and NBCn2). Topographical information derives mainly from study of AE1, abundant in erythrocytes, which suggests a dimeric or tetrameric arrangement, with subunits made up of 13 TM domains and re-entrant loops at TM9/10 and TM11/12. The N terminus exhibits sites for interaction with multiple proteins, including glycolytic enzymes, haemoglobin and cytoskeletal elements.

Anion exchangers

Systematic name	SLC4A1	SLC4A2	SLC4A3	SLC4A9
Common abbreviation	AE1	AE2	AE3	AE4
Nomenclature	Anion exchange protein 1	Anion exchange protein 2	Anion exchange protein 3	Anion exchange protein 4
Ensembl ID	ENSG00000004939	ENSG00000164889	ENSG00000114923	ENSG00000113073
Other names	Band 3, CD233	Non-erythroid band 3-like protein, BND3L	Neuronal band 3-like protein, cardiac/brain band 3-like protein, CAE3/BAE3	Sodium bicarbonate cotransporter 5
Endogenous substrates	Chloride, bicarbonate	Chloride, bicarbonate	Chloride, bicarbonate	–
Stoichiometry	1 Cl- (in) : 1 HCO3- (out)	1 Cl- (in) : 1 HCO3- (out)	1 Cl- (in) : 1 HCO3- (out)	–

Sodium-dependent HCO₃^- transporters

Systematic name	SLC4A4	SLC4A5	SLC4A7	SLC4A10
Common abbreviation	NBCe1	NBCe2	NBCn1	NBCn2
Nomenclature	Electrogenic sodium bicarbonate cotransporter 1	Electrogenic sodium bicarbonate cotransporter 4	Electroneutral sodium bicarbonate cotransporter 1	Electroneutral sodium bicarbonate cotransporter 2
Ensembl ID	ENSG00000080493	ENSG00000188687	ENSG00000033867	ENSG00000144290
Other names	Sodium bicarbonate cotransporter, kNBC1, NBC2, pNBC	NBC4	Sodium bicarbonate cotransporter 3, NBC3	Sodium-driven chloride bicarbonate exchanger, NCBE
Endogenous substrates	Sodium bicarbonate	Sodium bicarbonate	Sodium bicarbonate	Sodium bicarbonate
Stoichiometry	1 Na+: 2/3 HCO3- (out) or 1 Na+: CO32* (out) or 1 NaCO3- (out)	1 Na+: 2/3 HCO3- (out) or 1 Na+: CO32* (out) or 1 NaCO3- (out)	1 Na+: 1 HCO3- (out) or 1 Na+: CO32* (out) or 1 NaCO3- (out)	1 Na+: 1 HCO3- (out) or 1 Na+: CO32* (out) or 1 NaCO3- (out)

Systematic name	SLC4A8	SLC4A11
Common abbreviation	NDCBE	BTR1
Ensembl ID	ENSG00000050438	ENSG00000088836
Other names	Electroneutral Na+-driven Cl-HCO3 exchanger, k-NBC3	NaBC1, bicarbonate transporter-related protein 1
Endogenous substrates	Chloride, sodium bicarbonate	–
Stoichiometry	1 Na+: 2HCO3- (in) : 1 Cl- (out)	–

Further Reading

Alper SL (2009). Molecular physiology and genetics of Na⁺-independent SLC4 anion exchangers. J Exp Biol212: 1672–1683.

Romero MF, Fulton CM, Boron WF (2004). The SLC4 family of HCO₃^- transporters. Pflugers Arch447: 495–509.

SLC5 family of sodium-dependent transporters

Overview: The SLC5 family of sodium-dependent transporters includes, in mammals, the Na⁺/substrate co-transporters for choline, glucose, monocarboxylates, myo-inositol and iodide (Ferguson and Blakely, 2004; Wright and Turk, 2004; Ganapathy et al., 2008; Wright et al., 2011). 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 (Abramson and Wright, 2009).

Choline transporter

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 (Krishnaswamy and Cooper 2009). Through recapture of choline generated by the hydrolysis of ACh by acetylcholinesterase, CHT serves to maintain ACh synthesis within the presynaptic terminal (Ferguson and Blakely, 2004). 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 (Ferguson et al., 2004). 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 (Traiffort et al., 2005).

Common abbreviation	CHT
Systematic name	SLC5A7
Other names	CHT1, choline transporter 1
Ensembl ID	ENSG00000115665
Endogenous substrates	Choline
Synthetic substrates	Triethylcholine
Selective inhibitors (Ki)	HC-3 (1-5 nM)
Probes (KD)	[3H]-HC-3 (4-6 nM)
Stoichiometry	Na+: choline (variable stoichimetry); modulated by extracellular Cl- (Iwamoto et al., 2006)

K_i and K_D values for hemicholinium-3 listed in the table are for human CHT expressed in Xenopus laevis oocytes (Okuda and Haga, 2000), or COS-7 cells (Apparsundaram et al., 2000). Hemicholinium mustard is a substrate for CHT that causes covalent modification and irreversible inactivation of the transporter. Several exogenous substances (e.g. triethylcholine) that are substrates for CHT act as precursors to cholinergic false transmitters.

Hexose transporter family

Detailed characterisation of members of the hexose transporter family is limited to SGLT1, 2 and 3, which are all inhibited in a competitive manner by phlorizin, a natural dihydrocholine glucoside, that exhibits modest selectivity towards SGLT2 (see Wright et al., 2011 for an extensive review). SGLT1 is predominantly expressed in the small intestine, mediating the absorption of glucose, but also occurs in the brain, heart and in the late proximal straight tubule of the kidney. The expression of SGLT2 is almost exclusively restricted to the early proximal convoluted tubule of the kidney, where it is largely responsible for the renal reabsorption of glucose. SGLT3 is not a transporter but instead acts as a glucosensor generating an inwardly directed flux of Na⁺ that causes membrane depolarization (Diez-Sampedro et al., 2003).

Common abbreviation	SGLT1	SGLT2	SGLT3	SGLT4	SGLT5
Systematic name	SLC5A1	SLC5A2	SLC5A4	SLC5A9	SLC5A10
Other names	Sodium/glucose cotransporter 1, high affinity sodium-glucose cotransporter	Sodium/glucose cotransporter 2, low affinity sodium-glucose cotransporter	Low affinity sodium-glucose cotransporter, sodium/glucose cotransporter 3 (note, these previous names are a misnomer since SGLT3 is a glucosensor)	Sodium/glucose cotransporter 4	Sodium/glucose cotransporter 5
Ensembl ID	ENSG00000100170	ENSG00000140675	ENSG00000100191	ENSG00000117834	ENSG00000154025
Substrates	D-glucose, D-galactose	D-glucose	Ligands include D-glucose, 1-deoxynojirimycin, miglitol, miglustat, N-ethyl-1-deoxynojirimycin, and 1-deoxynojirimycin-1-sulfonic acid	D-glucose, D-mannose	D-glucose, D-galactose
Synthetic substrates	αMDG	αMDG	–	αMDG	–
Inhibitors (pIC50)	Dapaglifozin (5.9), canaglifozin (6.4), empaglifozin (5.1), remogliflozin (pKi = 5.4), sergliflozin (pKi = 5.1)	Dapagliflozin (9.0), canaglifozin (8.7), empaglifozin (8.5) remogliflozin (pKi = 7.9), sergliflozin (pKi = 6.8)	–	–	–
Stoichiometry	2 Na+: 1 glucose (Kanai et al., 1994)	1 Na+: 1 glucose (Hummel et al., 2011)	–	–	–

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 Wright et al., 2011 for a detailed quantification). Although SGLT1 and SGLT2 have been described as high- and low-affinity sodium glucose co-transporters, respectively, recent work suggests that they have a similar affinity for glucose under physiological conditions (Hummel et al., 2011). Selective blockers of SGLT2, and thus blocking ∼50% of renal glucose reabsorption, are in development for the treatment of diabetes (e.g. Chao and Henry, 2010).

Sodium iodide symporter, sodium-dependent multivitamin transporter and sodium-coupled monocarboxylate transporters

The sodium-iodide symporter (NIS) is an iodide transporter found principally in the thyroid gland where it mediates the accumulation of iodide within thyrocytes. Transport of iodide 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 iodide required for the synthesis of the thyroid hormones triiodothyronine (T₃) and thyroxine (T₄) (Bizhanova and Kopp, 2009). NIS is also expressed in the salivary glands, gastric mucosa, intestinal enterocytes and lactating breast. NIS mediates I^- absorption in the intestine and I^- secretion into the milk. SMVT is expressed on the apical membrane of intestinal enterocytes and colonocytes and is the main system responsible for biotin (vitamin H) and pantothenic acid (vitamin B₅) uptake in humans (Said, 2009). SMVT located in kidney proximal tubule epithelial cells mediates the reabsorption of biotin and pantothenic acid. SMCT1 (SLC5A8), which transports a wide range of monocarboxylates, is expressed in the apical membrane of epithelia of the small intestine, colon, kidney, brain neurones and the retinal pigment epithelium (Ganapathy et al., 2008). 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 (Ganapathy et al., 2008). SMCT1 is a high-affinity transporter whereas SMCT2 is a low-affinity transporter. The physiological substrates for SMCT1 and SMCT2 are lactate, pyruvate, propionate, and nicotinate in non-colonic tissues such as the kidney. SMCT1 is also likely to be the principal transporter for the absorption of nicotinate (vitamin B3) in the intestine and kidney (Gopal et al., 2005). In the small intestine and colon, the physiological substrates for these transporters are nicotinate and the short-chain fatty acids acetate, propionate, and butyrate that are produced by bacterial fermentation of dietary fiber (Miyauchi et al., 2004). 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 (Thangaraju et al., 2006a). SMCT1 also functions as a tumour suppressor in the colon as well as in various other non-colonic tissues (Ganapathy et al., 2009). The tumour-suppressive function of SMCT1 is based on its ability to transport pyruvate, an inhibitor of histone deacetylases, into cells in non-colonic tissues (Thangaraju et al., 2006b); in the colon, the ability of SMCT1 to transport butyrate and propionate, also inhibitors of histone deacetylases, underlies the tumour-suppressive function of this transporter (Gupta et al., 2006; Ganapathy et al., 2008; Ganapathy et al., 2009). The ability of SMCT1 to promote histone acetylase inhibition through accumulation of butyrate and propionate in immune cells is also responsible for suppression of dendritic cell development in the colon (Singh et al., 2010).

Common abbreviation	NIS	SMVT	SMCT1	SMCT2
Systematic name	SLC5A5	SLC5A6	SLC5A8	SLC5A12
Other names	Sodium/iodide cotransporter, sodium-iodide symporter	Sodium-dependent multivitamin transporter	Sodium-coupled monocarboxylate transporter 1, electrogenic sodium monocarboxylate cotransporter, sodium iodide-related cotransporter, apical iodide transporter (AIT)	Sodium-coupled monocarboxylate transporter 2, electroneutral sodium monocarboxylate cotransporter, low-affinity sodium-lactate cotransporter
Ensembl ID	ENSG00000105641	ENSG00000138074	ENSG00000139357	ENSG00000148942
Substrates	I-, thiocyanate, nitrate	Pantothenic acid, biotin, lipoic acid, I- (de Carvalho and Quick, 2011)	Butyrate, L-lactate, propionate, acetoacetate, α-ketoisocaproate, nicotinate, pyroglutamate, pyruvate, D-lactate, β-D-hydroxybutryrate, γ-hydroxybutyrate, β-L-hydroxybutryrate, acetate	Lactate, pyruvate, nicotinate
Synthetic substrates	Perchlorate, pertectnetate	–	Benzoate, salicylate, 5-aminosalicylate, 2-oxothiazolidine-4-carboxylate, dichloroacetate, 8-bromopyruvate	–
Inhibitors (pIC50)	–	–	Ibuprofen (4.2), ketoprofen, fenoprofen	–
Stoichiometry	2 Na+: 1 I- (Eskandari et al., 1997); 1 Na+: 1 ClO4- (Dohan et al., 2007)	2 Na+: 1biotin (or pantothenic acid) (Prasad et al., 2000)	2 Na+: 1 monocarboxylate (Coady et al., 2007)	–

I-, perchlorate, thiocyanate and nitrate are competitive substrate inhibitors of NIS (Dohan et al., 2007). α-Lipoic acid appears to act as a competitive substrate inhibitor of SMVT (Wang et al., 1999) and the anticonvulsant drugs primidone and carbamazepine competitively block the transport of biotin by brush border vesicles prepared from human intestine (Said et al., 1998).

Sodium myo-inositol cotransporter transporters

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 (Bissonnette et al., 2004). In the nephron, SMIT1 mediates myo-inositol uptake as a ‘compatible osmolyte’ when inner medullary tubules are exposed to increases in extracellular osmolality, whilst SMIT2 mediates the reabsorption of myo-inositol from the filtrate. In some species (e.g. rat, but not rabbit) apically located SMIT2 is responsible for the uptake of myo-inositol from the intestinal lumen (Aouameur et al., 2007).

Common abbreviation	SMIT1	SMIT2
Systematic name	SLC5A3	SLC5A11
Other names	Sodium/myo-inositol cotransporter (SMIT)	Sodium/myo-inositol cotransporter 2, sodium/glucose cotransporter6, kST1
Ensembl ID	ENSG00000198743	ENSG00000158865
Substrates	Myo-inositol, scyllo-inositol > L-fucose > L-xylose > L-glucose, D-glucose, alpha-methyl-D-glucopyranoside > D-galactose, D-fucose > D-xylose (Hager et al., 1995)	Myo-inositol = D-chiro-inositol> D-glucose > D-xylose > L-xylose (Coady et al., 2002)
Inhibitors	Phlorizin	Phlorizin
Stoichiometry	2 Na+:1 myo-inositol (Hager et al., 1995)	2 Na+:1 myo-inositol (Bourgeois et al., 2005)

The data tabulated are those for dog SMIT1 and rabbit SMIT2. SMIT2 transports D-chiro-inositol, but SMIT1 does not. In addition, whereas SMIT1 transports both D- and L-xylose and D- and L-fucose, SMIT2 transports only the D-isomers of these sugars (Hager et al., 1995; Coady et al, 2002). Thus the substrate specificities of SMIT1 (for L-fucose) and SMIT2 (for D-chiro-inositol) allow discrimination between the two SMITs. Human SMIT2 appears not to transport glucose (Lin et al., 2009).

Abbreviations: HC-3, hemicholinium-3; αMDG, α-methyl-D-glucose pyranoside

Further Reading

Abramson J, Wright EM (2009). Structure and function of Na(+)-symporters with inverted repeats. Curr Opin Struct Biol19: 425–432.

Amenta F, Tayebati SK (2008). Pathways of acetylcholine synthesis, transport and release as targets for treatment of adult-onset cognitive dysfunction. Curr Med Chem15: 488–498.

Bailey CJ (2011). Renal glucose reabsorption inhibitors to treat diabetes. Trends Pharmacol Sci32: 63–71.

Bazalakova MH, Blakely RD (2006). The high-affinity choline transporter: a critical protein for sustaining cholinergic signaling as revealed in studies of genetically altered mice. Handb Exp Pharmacol175: 525–544.

Bizhanova A, Kopp P (2009). The sodium-iodide symporter NIS and pendrin in iodide homeostasis of the thyroid. Endocrinology, 150: 1084–1090.

Boldys A, Okopien B (2009). Inhibitors of type 2 sodium glucose co-transporters-a new strategy for diabetes treatment. Pharmacol Rep61: 778–784.

Chao EC, Henry RR (2010). SGLT2 inhibiton – a novel strategy for diabetes treatment. Nat Rev Drug Dev9: 511–559.

Ferguson SM, Blakely RD (2004). The choline transporter resurfaces: new roles for synaptic vesicles. Mol Interv4: 22–37.

Ganapathy V, Thangaraju M, Gopal E, Martin PM, Itagaki S, Miyauchi S, Prasad PD (2008). Sodium-coupled monocarboxylate transporters in normal tissues and in cancer. AAPS J10: 193–199.

Ganapathy V, Thangaraju M, Prasad PD (2009). Nutrient transporters in cancer: relevance to Warburg hypothesis and beyond. Pharmacol Ther121: 29–40.

Ghosh RK, Ghosh SM, Chawla S, Jasdanwala SA (2011). SGLT2 inhibitors: a new emerging therapeutic class in the treatment of type 2 diabetes mellitus. J Clin Pharmacol doi: 10-1177/091270011400604.x

Kinne RK, Castaneda F (2011). SGLT inhibitors as new therapeutic tools in the treatment of diabetes Handb Exp Pharmacol203: 105–126.

Okuda T, Haga T (2003). High-affinity choline transporter. Neurochem Res28: 483–488.

Ribeiro FM, Black SA, Prado VF, Rylett RJ, Ferguson SS, Prado MA. (2006). The “ins” and “outs” of the high-affinity choline transporter CHT1. J Neurochem97: 1–12.

Sabino-Silva R, Mori RC, David-Silva A, Okamoto MM, Freitas HS, Machado UF. (2010).The Na⁺/glucose cotransporters: from genes to therapy. Braz J Med Biol Res43: 1019–1026.

Said HM (2009). Cell and molecular aspects of human intestinal biotin absorption. J Nutr139: 158–162.

Sarter M, Parikh V (2005). Choline transporters, cholinergic transmission and cognition. Nat Rev Neurosci6: 48–56.

Uldry M, Thorens B (2004). The SLC2 family of facilitated hexose and polyol transporters. Pflugers Arch447: 480–489.

Wright EM, Loo DD, Hirayama BA (2004). Surprising versatility of Na⁺-glucose cotranporters: SCL5. Physiology19: 370–376.

Wright EM, Loo DD, Hirayama BA (2011). Biology of human sodium glucose transporters. Physiol Rev91: 733–794.

Wright EM, Turk E (2004). The sodium/glucose cotransport family SLC5. Pflügers Arch447: 510–518.

SLC6 neurotransmitter transporter family

Overview: Members of the solute carrier family 6 (SLC6) of sodium- and (sometimes chloride-) dependent neurotransmitter transporters (see Chen et al., 2004; Bröer, 2006; Kristensen et al., 2011) are primarily plasma membrane located and may be divided into four subfamilies that transport monoamines, GABA, glycine and neutral amino acids, plus the related bacterial NSS transporters (see Saier et al., 2009). 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 LeuT_Aa, a Na⁺-dependent amino acid transporter from Aquiflex aeolicus (Yamashita et al., 2005) and in several other transporter families structurally related to LeuT (Forrest and Rudnick, 2009).

Monoamine transporter subfamily

Monoamine neurotransmission is limited by perisynaptic transporters. Presynaptic monoamine transporters allow recycling of synaptically released noradrenaline, dopamine and 5-hydroxytryptamine.

Common abbreviation	NET	DAT	SERT
Systematic name	SLC6A2	SLC6A3	SLC6A4
Other names	NAT1	DAT1	5-HTT, SERT1
Ensembl ID	ENSG00000103546	ENSG00000142319	ENSG00000108576
Endogenous substrates	Noradrenaline, adrenaline, dopamine	Dopamine, adrenaline, noradrenaline	5-HT
Synthetic substrates	Amphetamine, methamphetamine, MPP+	Amphetamine, methamphetamine, MPP+	p-Chloroamphetamine, MDMA
Selective inhibitors (pKi)	Mazindol (8.9), nisoxetine (8.4), nomifensine (8.1), reboxetine (8.0, Wong et al., 2000)	Mazindol (8.0), WIN35428 (7.9), GBR12935 (7.6)	Paroxetine (9.6, Tatsumi et al., 1997), sertraline (9.1), fluoxetine (8.5, Tatsumi et al., 1997)
Probes	[3H]-Mazindol (0.5 nM), [3H]-nisoxetine (4 nM)	[3H]-GBR12935 (3 nM, Pristupa et al., 1994), [3H]-WIN35428 (10 nM, Pristupa et al., 1994)	[3H]-Paroxetine (0.2 nM), [3H]-citalopram (5 nM)
Predicted stoichiometry	1 Noradrenaline: 1 Na+:1 Cl- (Gu et al., 1996)	1 Dopamine:1–2 Na+:1 Cl- (Gu et al., 1994)	1 5-HT:1 Na+:1 Cl- (in), + 1 K+ (out) (Talvenheimo et al., 1983)

[¹²⁵I]-RTI55 labels all three monoamine transporters (NET, DAT and SERT) with affinities between 0.5 and 5 nM. Cocaine is an inhibitor of all three transporters with pK_i 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 (Singh et al., 2007).

GABA transporter subfamily

The activity of GABA-transporters located predominantly upon neurones (GAT1), glia (GAT3) or both (GAT2, BGT1) serves to terminate phasic GABA-ergic transmission, maintain low ambient extracellular concentrations of GABA, and recycle GABA for reuse by neurones. Nonetheless, ambient concentrations of GABA are sufficient to sustain tonic inhibition mediated by high affinity GABA_A receptors in certain neuronal populations (Semyanov et al., 2004). 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 (Madsen et al., 2010). 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 (Chen et al., 2004; Han et al., 2006). CT1, which transports creatine, has a ubiquitous expression pattern, often co-localizing with creatine kinase (Chen et al., 2004).

Common abbreviation	GAT1	GAT2	GAT3
Systematic name	SLC6A1	SLC6A13	SLC6A11
Other names	mGAT1, GAT-A	mGAT3	mGAT4, GAT-B
Ensembl ID	ENSG00000157103	ENSG00000010379	ENSG00000132164
Endogenous substrates	GABA	GABA, β-alanine	GABA, β-alanine
Synthetic substrates	Nipecotic acid, guvacine	Nipecotic acid, guvacine	Nipecotic acid, guvacine
Selective inhibitors (IC50)	NNC-711 (0.14–1.4 µM), SKF89976A (0.13 µM), CI-966 (0.26 µM), tiagabine (0.11 – 2.4 µM), (R/S) EF-1500 (2 – 13 µM) (R)-EF1502 (4 µM – 8.9 µM), LU32-176B (4 µM), (S)-EF-1502 (120 µM – > 250 µM)	SNAP-5114 (20 µM)	SNAP-5114 (6.6 µM)
Probes	[3H]Tiagabine	–	–
Predicted stoichiometry	2 Na+: 1Cl-: 1GABA	2 Na+: 1Cl-:1GABA	≥2 Na+: 2 Cl-: 1GABA

Common abbreviation	BGT1	TauT	CT1
Systematic name	SLC6A12	SLC6A6	SLC6A8
Other names	mGAT2	Sodium- and chloride-dependent taurine transporter	Sodium- and chloride-dependent creatine transporter 1, CRT, CRTR, SLC6A10
Ensembl ID	ENSG00000111181	ENSG00000131389	ENSG00000130821
Endogenous substrates	GABA, betaine	Taurine, β-alanine, GABA (Anderson et al., 2009)	Creatine
Synthetic substrates	–	–	–
Selective inhibitors (IC50)	NNC052090 (1.4 µM), (R)-EF-1502 (22 µM–180 µM), (R/S) EF-1500 (26 µM) (S)-EF-1502 (34 µM – > 250 µM), LU32-176B (>100 µM)		–
Predicted stoichiometry	3 Na+: 1 (or 2) Cl-: 1 GABA	2 Na+: 1Cl-: 1 taurine	Probably 2 Na+: 1Cl-: 1 creatine

The IC₅₀ values for GAT1-3 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 (Kvist et al. 2009). SNAP-5114 is only weakly selective for GAT2 and GAT3, with IC₅₀ values in the range 22 to >30 µM at GAT1 and BGT1, whereas NNC052090 has at least an order of magnitude selectivity for BGT1 [see Schousboe et al. (2004b) and Clausen et al. (2006) for reviews]. (R)-(1-{2-[tris(4-methoxyphenyl)methoxy]ethyl}pyrrolidin-2-yl)acetic acid is a compound that displays 20-fold selectivity for GAT3 over GAT1 (Fülep et al., 2006). In addition to the inhibitors listed, EGYT3886 is a moderately potent, though non-selective, inhibitor of all cloned GABA transporters (IC₅₀ = 26–46 µM; Dhar et al., 1994). Diaryloxime and diarylvinyl ether derivatives of nipecotic acid and guvacine that potently inhibit the uptake of [³H]GABA into rat synaptosomes have been described (Knutsen et al., 1999). Several derivatives of exo-THPO (e.g. N-methyl-exo-THPO and N-acetyloxyethyl-exo-THPO) demonstrate selectivity as blockers of astroglial, versus neuronal, uptake of GABA [see Schousboe et al. (2004a) and Clausen et al. (2006) for reviews]. GAT3 is inhibited by physiologically relevant concentrations of Zn²⁺ (Cohen-Kfir et al., 2005). TauT transports GABA, but with low affinity, but CT1 does not, although it can be engineered to do so by mutagenesis guided by LeuT as a structural template (Dodd and Christie, 2007). Although inhibitors of creatine transport by CT1 (e.g.β-guanidinopropionic acid, cyclocreatine, γ-guanidino sulphonic acid) are known (e.g. Dai et al., 1999) they are insufficiently characterized to be included in the table.

Glycine transporter subfamily

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 Supplisson and Roux, 2002; Eulenburg et al., 2005; Betz et al., 2006; Gomeza et al., 2006 for reviews). GlyT1 transporter isoforms expressed in glia surrounding glutamatergic synapses regulate synaptic glycine concentrations influencing NMDA receptor-mediated neurotransmission (Bergeron et al., 1998; Gabernet et al., 2005), but also are important, in early neonatal life, for regulating glycine concentrations at inhibitory glycinergic synapses (Gomeza et al., 2003a). 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 (Gomeza et al., 2003a, Tsai et al., 2004). 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 (Yee et al., 2006). 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 (Gomeza et al., 2003b; Rousseau et al., 2008). Mice in which GlyT2 has been deleted develop a fatal hyperekplexia phenotype during the second postnatal week (Gomeza et al., 2003b) and mutations in the human gene encoding GlyT2 (SLC6A5) have been identified in patients with hyperekplexia (reviewed by Harvey et al., 2008). 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 (Chen et al., 2004). ATB⁰⁺ is expressed in various peripheral tissues (Chen et al., 2004). By contrast PROT (SLC6A7), which is expressed only in brain in association with a subset of excitatory nerve terminals, shows specificity for the transport of L-proline.

Common abbreviation	GlyT1	GlyT2	ATB0,+	PROT
Systematic name	SLC6A9	SLC6A5	SLC6A14	SLC6A7
Other names	Glycine transporter 1	Glycine transporter 2	Sodium- and chloride-dependent neutral and basic amino acid transporter B0,+	Sodium-dependent proline transporter
Ensembl ID	ENSG00000196517	ENSG00000165970	ENSG00000087916	ENSG00000011083
Endogenous substrates	Glycine, sarcosine	Glycine	Iso > leu, met > phe > trp > val > ser (Sloan and Mager, 1999), β-alanine (Anderson et al., 2008, 2009)	L-Proline
Synthetic substrates	–	–	BCH, 1-methytryptophan (Karunakaran et al., 2008), valganciclovir (Umapathy et al., 2004), zwitterionic or cationic NOS inhibitors (Hatanaka et al., 2001)	–
Selective inhibitors (IC50)	(R)-NFPS (ALX 5407) (0.8 – 3 nM), SSR-103800 (2 nM), N-methyl-SSR-504734 (2.5 nM), NFPS (3 – 100 nM), LY2365109 (16 nM), SSR504734 (18 – 314 nM), GSK931145 (26 nM); RG1678 (30 nM); SB-733993 (31 nM); NPTS (37 nM), Org 24598	ALX 1393, ALX 1405, Org 25543 (20 nM)	α-methyltryptophan (250 µM, Karunakaran et al., 2008)	LP-403812 (0.11 µM, Yu et al., 2009)
Probes (Kd)	[3H]-(R)-NPTS (1 nM), [3H]-GSK931145 (1.7 nM), [35S]-ACPPB (2 nM), [3H]-SB-733993 (2.2 nM), [3H]-N-methyl-SSR504734 (3.3 -8.1 nM), [3H]-NFPS (7-21 nM)	–	–	–
Predicted stoichiometry	2 Na+: 1 Cl-: 1 glycine	3 Na+: 1 Cl-: 1 glycine	2-3 Na+: 1 Cl-: 1 amino acid (Sloan and Mager, 1999)	Probably 2 Na+: 1 Cl-: 1 L-proline

Sarcosine is a selective transportable inhibitor of GlyT1 and also a weak agonist at the glycine binding site of the NMDA receptor (Zhang et al., 2009), but has no effect on GlyT2. This difference has been attributed to a single glycine residue in TM6 (serine residue in GlyT2) (Vandenberg et al., 2007). Inhibition of GLYT1 by the sarcosine derivatives NFPS, NPTS and Org24598 is non-competitive (Mallorga et al., 2003; Mezler et al., 2008). IC₅₀ values for Org 24598 reported in the literature vary, most likely due to differences in assay conditions (Brown et al., 2001; Mallorga et al., 2003). The tricyclic antidepressant amoxapine weakly inhibits GlyT2 (IC₅₀ 92 µM) with approximately 10-fold selectivity over GlyT1 (Nunez et al., 2000). The endogenous lipids arachidonic acid and anandamide exert opposing effects upon GlyT1a, inhibiting (IC₅₀∼ 2 µM) and potentiating (EC₅₀∼ 13 µM) transport currents, respectively (Pearlman et al., 2003). N-arachidonyl-glycine, N-arachidonyl-γ-aminobutyric acid and N-arachidonyl-D-alanine have been described as endogenous non-competitive inhibitors of GlyT2a, but not GlyT1b (Wiles et al., 2006; Edington et al., 2009; Jeong et al., 2010). Protons (Aubrey et al., 2000) and Zn²⁺ (Ju et al., 2004) act as non-competitive inhibitors of GlyT1b, with IC₅₀ values of ∼100 nM and ∼10 µM respectively, but neither ion affects GlyT2 (reviewed by Vandenberg et al., 2004). Glycine transport by GLYT1 is inhibited by lithium, whereas GLYT2 transport is stimulated (both in the presence of Na⁺) (Pérez-Siles et al. 2011).

Neutral amino acid transporter subfamily

Certain members of neutral amino acid transport family are expressed upon the apical surface of epithelial cells and are important for the absorption of amino acids from the duodenum, jejunum and ileum and their reabsorption within the proximal tubule of the nephron (i.e. B⁰AT1 (SLC6A19), SLC6A17, SLC6A18, SLC6A20). Others may function as transporters for neurotransmitters or their precursors (i.e. B⁰AT2, SLC6A17) (Bröer, 2008).

Common abbreviation	B0AT1	BoAT2	B0AT3
Systematic name	SLC6A19	SLC6A15	SLC6A18
Other names	B0 neutral amino acid transporter	NTT73, v7-3, SBAT1	XT2, XTRP2
Ensembl ID	ENSG00000174358	ENSG00000072041	ENSG00000164363
Endogenous substrates	Leu, met, iso, val > asn, phe, ala, ser > thr, gly, pro (Bröer et al., 2006)	Pro > ala, val, met, leu > iso, thr, asn, ser, phe > gly (Bröer et al., 2006)	Ala, gly > met, phe, leu, his, gln (Vanslambrouck et al. 2010)
Predicted stoichiometry	1 Na: 1 amino acid (Böhmer et al., 2005)	1 Na: 1 amino acid (Bröer et al., 2006)	Na+- and Cl- -dependent transport (Singer et al., 2009)

Systematic name	SLC6A16	SLC6A17	SLC6A20
Common abbreviation	–	–	SIT1
Other names	NTT5	NTT4, XT1, XTRP1	XTRP3, rB21A, IMINO, XT3, sodium/imino-acid transporter 1
Ensembl ID	ENSG00000063127	ENSG00000197106	ENSG00000163817
Endogenous substrates	Unknown	Leu, met, pro > cys, ala, gln, ser > his, gly (Zaia and Reimer, 2009)	Proline
Predicted stoichiometry	–	Na+-dependent, Cl--indpendent transport (Zaia and Reimer, 2009)	2 Na+: 1 Cl-: 1 imino acid (Bröer et al., 2009)

Mutations in B⁰AT1 are associated with Hartnup disorder.

Abbreviations: ACPPB, (S)-2-amino-4-chloro-N-(1-(4-phenyl-1-(propylsulfonyl)piperidin-4-yl)ethyl)benzamide; ALX 1393, O-[2-benzyloxyphenyl-3-flurophenyl]methyl-L-serine; ALX 1405, structure not available; BCH, 2-aminobicyclo-[2.2.1]-heptane-2-carboxylic acid; CI966, [1-[2-[bis-4(trifluromethyl)phenyl]methoxy]ethyl]-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid; EF1500, N-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3-hydroxy-4-amino-4,5,6,7-tetrahydrobenzo[d]isoxazol-3-ol; EF1502, N-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3-hydroxy-4-(methylamino)4,5,6,7,tetrabenzo[d]isoxazol-3-ol; EGYT3886, (-)-2-phenyl-2-[(dimethylamino)ethoxy]-(1R)-1,7,7-trimethylbicyclo[2.2.1]heptane; exo-THPO, 3-hydroxy-4-amino-4,5,6,7-tetrahydro-1,2-benzisoxazol; GBR12935, 1-(2-[diphenylmethoxy]ethyl)-4-(3-phenylpropyl)piperazine; GSK931145, N-{[1-(dimethylamino)cyclopentyl](phenyl)methyl}-2,6-dimethylbenzamide; LP-403812, see Yu et al. (2009) for structure; LU32-176B, N-[4,4-bis(4-fluorophenyl)-butyl]-3-hydroxy-4-amino-4,5,6,7-tetrahydrobenzo[d]isoxazol-3-ol; LY2365109, {[2-(4-benzo[1,3]dioxol-5-yl-2-tert-butylphenoxy)ethyl]-methylamino}-acetic acid; MDMA, 3,4-methylenedioxymethamphetamine; MPP⁺, 1-methyl-4-phenylpyridinium; NFPS, N-[3-(4′-fluorophenyl)-3-(4′-phenylphenoxy)propyl]sarcosine; NNC052090, 1-(3-(9H-carbazol-9-yl)-1-propyl)-4-(2-methoxyphenyl)-4-piperidinol; NNC711, 1-2-(((diphenylmethylene)amino)oxy)ethyl)-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid hydrochloride; NPTS, (N-[3-phenyl-3-(4′-(4-toluoyl) phenoxy)propyl]sarcosine; Org 24598, R-(-)-N-[3-[(4-triflouromethyl)phenoxy]-3-phenyl-propylglycine; Org 25543, 4-benzyloxy-3,5-dimethoxy-N-[1-(dimethylaminocyclopentyl) methyl] benzamide; RG1678, [4-(3-fluoro-5-trifluoromethylpyridin-2-yl)piperazin-1-yl][5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methylethoxy)phenyl]methanone; RTI55, 2β-carbomethoxy-3β-(4-iodophenyl) tropane (also known as β-CIT); SB-733993, (2R)-3-[(2R,6S)-2,6-dimethylpiperidin-1-yl]-2-hydroxy-S-(naphthalen-1-yl)propane-1-sulfonamido; SKF89976A, 1-(4,4-diphenyl-3-butenyl)-3-piperidinecarboxylic acid; SSR103800, structure not available; SSR504734, 2-chloro-[N-(S)-phenyl[(2S)-piperidin-2-yl]methyl]-3-trifluoromethyl benzamide; WIN35428, 2β-carboxymethy-3β-(4-fluorophenyl)tropane (also known as β-CFT).

Further Reading

Aragón C, Lopez-Córcuera B (2005). Glycine transporters: crucial roles of pharmacological interest revealed by gene deletion. Trends Pharmacol Sci26: 283–286.

Betz H, Gomeza J, Scholze P, Eulenberg V (2006). Glycine transporters: essential regulators of synaptic transmission. J Neurochem97: 1600–1610.

Bridges TM, Williams R, Lindsley CW (2008). Design of potent GlyT1 inhibitors: in vitro and in vivo profiles. Curr Opin Mol Ther10: 591–601.

Bröer S (2006). The SLC6 orphans are forming a family of amino acid transporters. Neurochen Int48: 559–567.

Bröer S (2008). Apical transporters for neutral amino acids: physiology and pathophysiology. Physiology23: 95–103.

Chen N-H, Reith MEA, Quick MW (2004). Synaptic uptake and beyond: the sodium and chloride dependent neurotransmitter transporter family SLC6. Pflügers Archiv447: 519–531.

Christie DL (2007). Functional insights into the creatine transporter. Subcell Biochem46: 99–118.

Clausen RP, Madsen K, Larsson OM, Frolund B, Krogsgaard-Larsen P, Schousboe A (2006). Structure-activity relationship and pharmacology of gamma-aminobutyric acid (GABA) transport inhibitors. Adv Pharmacol54: 265–284.

Dai W et al. (1999). Arch Biochem Biophys361: 75–84.

Dalby NO (2003). Inhibition of gamma-aminobutyric acid uptake: anatomy, physiology and effects against epileptic seizures. Eur J Pharmacol479: 127–137.

Daws LC (2009). Unfaithful neurotransmitter transporters: focus on serotonin uptake and implications for antidepressant efficacy. Pharmacol Ther121: 89–99.

Dohi T, Morita K, Kitayama T, Motoyama N, Morioka N (2009). Glycine transporter inhibitors as a novel drug discovery strategy for neuropathic pain. Pharmacol Ther123: 54–79.

Eulenburg V, Armsen W, Betz H, Gomeza J (2005). Glycine transporters: essential regulators of neurotransmission. Trends Biochem Sci30: 325–333.

Foster JD, Cervinski MA, Gorentla BK, Vaughan RA (2006). Regulation of the dopamine transporter by phosphorylation. Handb Exp Pharmacol 197–214.

Gadia A, Lopez-Colome AM (2001). Glial transporters for glutamate, glycine and GABA: II. GABA transporters. J Neurosci Res63: 461–468.

Gasnier B (2004). The SLC32 transporter, a key protein for the synaptic release of inhibitory amino acids. Pflügers Archiv447: 756–759.

Gether U, Andersen PH, Larsson OM, Schousboe A (2007). Neurotransmitter transporters: molecular function of important drug targets. Trends Pharmacol Sci27: 375–383.

Gomeza J, Armsen W, Betz H, Eulenburg V (2006). Lessons from the knocked-out glycine transporters. Handb Exp Pharmacol175: 457–483.

Gonzalez-Burgos G (2010). GABA transporter GAT1: a crucial determinant of GABA_B receptor activation in cortical circuits? Adv Pharmacol58:175–204.

Han X, Patters AB, Jones DP, Zelikovic I, Chesney RW (2006). The taurine transporter: mechanisms of regulation. Acta Physiol (Oxf)187: 61–73.

Harsing LG Jr, Juranyi Z, Gacsalyi I, Tapolcsanyi P, Czompa A, Matyus P (2006). Glycine transporter type-1 and its inhibitors. Curr Med Chem13: 1017–1044.

Harvey RJ, Topf M, Harvey K, Rees MI (2008).The genetics of hyperekplexia: more than startle! Trends Genet24: 439–447.

Hashimoto K (2011). Glycine transporter-1: a new potential therapeutic target for schizophrenia. Curr Pharm Des17:112–120.

Hog S, Greenwood JR, Madsen KB, Larsson OM, Frolund B, Schousboe A et al. (2006). Structure-activity relationships of selective GABA uptake inhibitors. Curr Top Med Chem6: 1861–1882.

Horstmann S, Binder EB (2009). Pharmacogenomics of antidepressant drugs. Pharmacol Ther124: 57–73.

Javitt DC (2009). Glycine transport inhibitors for the treatment of schizophrenia: symptom and disease modification. Curr Opin Drug Discov Devel12:468–478.

Kanner BI (2006). Structure and function of sodium-coupled GABA and glutamate transporters. J Membr Biol213: 89–100.

Karunakaran S et al. (2008). Biochem J414: 343–555.

Kristensen AS, Andersen J, Jørgensen TN, Sørensen L, Eriksen J, Claus J. Loland CJ et al. (2011). SLC6 Neurotransmitter transporters: structure, function, and regulation. Pharmacol Rev63: 585–640.

Kulig K, Szwaczkiewicz M (2008). The role of structure activity relationship studies in the search for new GABA uptake inhibitors. Mini Rev Med Chem8: 1214–1223.

Lechner SM (2006). Glutamate-based therapeutic approaches: inhibitors of glycine transport. Curr Opin Pharmacol6: 75–81.

Madsen KK, White HS, Schousboe A (2010). Neuronal and non-neuronal GABA transporters as targets for antiepileptic drugs. Pharmacol Ther125: 394–401.

Mazei-Robinson MS, Blakely RD (2006). ADHD and the dopamine transporter: are there reasons to pay attention? Handb Exp Pharmacol175: 373–415.

Millan MJ (2006). Multi-target strategies for the improved treatment of depressive states: conceptual foundations and neuronal substrates, drug discovery and therapeutic application. Pharmacol Ther110: 135–370.

Moltzen EK, Bang-Andersen B (2006). Serotonin reuptake inhibitors: the corner stone in treatment of depression for half a century–a medicinal chemistry survey. Curr Top Med Chem6: 1801–1823.

Richerson GB, Wu Y (2004). Role of the GABA transporter in epilepsy. Adv Exp Med Biol548: 76–91.

Runyon SP, Carroll FI (2006). Dopamine transporter ligands: recent developments and therapeutic potential. Curr Top Med Chem6: 1825–1843.

Sałat K, Kulig K. (2011). GABA transporters as targets for new drugs. Future Med Chem3: 211–222.

Saier MH, Yen MR, Noto K, Tamang DG, Elkan C (2009). The Transporter Classification Database: recent advances. Nucleic Acids Res, 37: D274–D278.

Sarup A, Larsson OM, Schousboe A (2003). GABA Transporters and GABA-Transaminase as Drug Targets. Curr Drug Target CNS Neurol Disord2: 269–277.

Schousboe A, Sarup A, Bak LK, Waagepetersen HS, Larsson OM (2004a). Role of astrocytic transport processes in glutamatergic and GABAergic neurotransmission. Neurochem Int45: 521–527.

Schousboe A, Sarup A, Larsson OM, White HS (2004b). GABA transporters as drug targets for modulation of GABAergic activity. Biochem Pharmacol68: 1557–1563.

Schousboe A, Madsen KK, White HS (2011). GABA transport inhibitors and seizure protection: the past and future. Future Med Chem3: 183–187.

Semyanov A, Walker MC, Kullmann DM, Silver RA (2004). Tonically active GABA_A receptors: modulating gain and maintaining the tone. Trends Neurosci27: 262–269.

Soudijn W, van Wijngaarden I (2000). The GABA transporter and its inhibitors. Curr Med Chem7: 1063–1079.

Supplisson S, Roux MJ (2002). Why glycine transporters have different stoichiometries. FEBS Lett529: 93–101.

Sur C, Kinney GG (2007). Glycine transporter 1 inhibitors and modulation of NMDA receptor-mediated excitatory neurotransmission. Curr Drug Targets8: 643–649.

Torres GE, Gainetdinov RR, Caron MG (2003). Plasma membrane monoamine transporters: structure, regulation and function. Nat Rev Neurosci4: 13–25.

Vandenberg RJ, Ju P, Aubrey KR, Ryan RM, Mitrovic AD (2004). Allosteric modulation of neurotransmitter transporters at excitatory synapses. Eur J Pharm Sci23: 1–11.

Wang CI, Lewis RJ (2010). Emerging structure-function relationships defining monoamine NSS transporter substrate and ligand affinity. Biochem Pharmacol79: 1083–1091.

Williams JM, Galli A (2006). The dopamine transporter: a vigilant border control for psychostimulant action. Handb Exp Pharmacol: 215–232.

Wolkenberg SE, Sur C (2010). Recent progress in the discovery of non-sarcosine based GlyT1 inhibitors. Curr Top Med Chem10: 170–186.

Zafra F, Giménez C (2008). Glycine transporters and synaptic function. IUBMB Life60: 810–817.

SLC8 family of sodium/calcium exchangers

Overview: the sodium/calcium exchangers (NCX) use the extracellular sodium concentration to facilitate the extrusion of calcium out of the cell. Alongside the plasma membrane Ca²⁺-ATPase (PMCA, see Page S219) and sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase (SERCA, see Page S219), as well as the sodium/potassium/calcium exchangers (NKCX, SLC24 family, see Page S255), NCX allow recovery of intracellular calcium back to basal levels after cellular stimulation. When intracellular sodium ion levels rise, for example, following depolarisation, these transporters can operate in the reverse direction to allow calcium influx and sodium efflux, as an electrogenic mechanism. Structural modelling suggests the presence of 9 TM segments, with a large intracellular loop between the fifth and sixth TM segments.

Nomenclature	Sodium/calcium exchanger 1	Sodium/calcium exchanger 2	Sodium/calcium exchanger 3
Systematic name	SLC8A1	SLC8A2	SLC8A3
Preferred abbreviation	NCX1	NCX2	NCX3
Ensembl ID	ENSG00000183023	ENSG00000118160	ENSG00000100678
Stoichiometry	3 Na+ (in) : 1 Ca2+ (out)	–	–
	or 4 Na+ (in) : 1 Ca2+ (out) (Dong et al., 2002)
	Reverse mode 1 Ca2+ (in): 1 Na+ (out)

Although subtype-selective inhibitors of NCX function are not widely available, 3,4-dichlorobenzamil and CBDMB act as non-selective NCX inhibitors, while SEA0400, KB-R7943 and SN6 act to inhibit NCX function selectively in the reverse mode.

Abbreviations: CBDMB, 3-amino-6-chloro-5-[(4-chlorophenyl)methylamino]-N-[[2-[(2,4-dimethylphenyl)methyl]hydrazinyl]methylidene]pyrazine-2-carboxamide; KB-R7943, methanesulfonic acid; 2-[4-[(4-nitrophenyl)methoxy]phenyl]ethylcarbamimidothioate; SEA0400, 2-[4-[(2,5-difluorophenyl)methoxy]phenoxy]-5-ethoxyaniline; SN6, N-[4-[(1-methylpyridin-1-ium-4-yl)amino]phenyl]-4-[(1-methylquinolin-1-ium-4-yl)amino]benzamide, also known as SN6999

Further Reading

Annunziato L, Pignataro G, Di Renzo GF (2004). Pharmacology of brain Na⁺/Ca²⁺ exchanger: from molecular biology to therapeutic perspectives. Pharmacol Rev56: 633–654.

Gabellini N (2004). Transcriptional regulation by cAMP and Ca²⁺ links the Na⁺/Ca²⁺ exchanger 3 to memory and sensory pathways. Mol Neurobiol30: 91–116.

Lytton J (2007). Na⁺/Ca²⁺ exchangers: three mammalian gene families control Ca²⁺ transport. Biochem J406: 365–382.

Quednau BD, Nicoll DA, Philipson KD (2004). The sodium/calcium exchanger family-SLC8. Pflugers Arch447: 543–548.

Watanabe Y, Koide Y, Kimura J (2006). Topics on the Na⁺/Ca²⁺ exchanger: pharmacological characterization of Na⁺/Ca²⁺ exchanger inhibitors. J Pharmacol Sci102: 7–16.

Zhang YH, Hancox JC (2009). Regulation of cardiac Na⁺-Ca²⁺ exchanger activity by protein kinase phosphorylation – still a paradox? Cell Calcium45: 1–10.

SLC9 family of sodium/hydrogen exchangers

Overview: sodium/hydrogen exchangers or sodium/proton antiports are a family of transporters that maintain cellular pH by utilising the sodium gradient across the plasma membrane to extrude protons produced by metabolism, in a stoichiometry of 1 Na⁺ (in) : 1 H⁺ (out). Several isoforms, NHE6, NHE7, NHE8 and NHE9 appear to locate on intracellular membranes (Miyazaki et al., 2001; Numata and Orlowski, 2001; Nakamura et al., 2005). 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. NHE2 and NHE3 are highly expressed in the intestine and kidneys and regulate sodium movements in those tissues. NHE10 is present in sperm (Wang et al., 2003) and osteoclasts (Lee et al., 2008); gene disruption results in infertile male mice (Wang et al., 2003).

Nomenclature	Systematic name	Common abbreviation	Ensembl ID	Other names
Sodium/hydrogen exchanger 1	SLC9A1	NHE1	ENSG00000090020	Na+/H+ antiporter, amiloride-sensitive, APNH
Sodium/hydrogen exchanger 2	SLC9A2	NHE2	ENSG00000115616
Sodium/hydrogen exchanger 3	SLC9A3	NHE3	ENSG00000066230
Sodium/hydrogen exchanger 4	SLC9A4	NHE4	ENSG00000180251
Sodium/hydrogen exchanger 5	SLC9A5	NHE5	ENSG00000135740
Sodium/hydrogen exchanger 6	SLC9A6	NHE6	ENSG00000198689
Sodium/hydrogen exchanger 7	SLC9A7	NHE7	ENSG00000065923
Sodium/hydrogen exchanger 8	SLC9A8	NHE8	ENSG00000197818
Sodium/hydrogen exchanger 9	SLC9A9	NHE9	ENSG00000181804
Sodium/hydrogen exchanger 10	SLC9A10	NHE10	ENSG00000172139	Sperm-specific Na+/H+ exchanger, sNHE
Sodium/hydrogen exchanger 11	SLC9A11	NHE11	ENSG00000162753

Analogues of the non-selective cation transport inhibitor amiloride appear to inhibit NHE function through competitive inhibition of the extracellular Na⁺ binding site. The more selective amiloride analogues MPA and EIPA exhibit a rank order of affinity of inhibition of NHE1 > NHE2 > NHE3 (Counillon et al., 1993; Tse et al., 1993a, 1993b).

Abbreviations: EIPA, 3-amino-6-chloro-N-(diaminomethylidene)-5-[ethyl(propan-2-yl)amino]pyrazine-2-carboxamide; MPA, 3-amino-6-chloro-N-(diaminomethylidene)-5-[methyl(propyl)amino]pyrazine-2-carboxamide

Further Reading

Casey JR, Grinstein S, Orlowski J (2010). Sensors and regulators of intracellular pH. Nat Rev Mol Cell Biol11: 50–61.

Kato A, Romero MF (2011). Regulation of electroneutral NaCl absorption by the small intestine. Annu Rev Physiol73: 261–281.

Kemp G, Young H, Fliegel L (2008). Structure and function of the human Na⁺/H⁺ exchanger isoform 1. Channels (Austin)2: 329–336.

Orlowski J, Grinstein S (2004). Diversity of the mammalian sodium/proton exchanger SLC9 gene family. Pflugers Arch447: 549–565.

Slepkov ER, Rainey JK, Sykes BD, Fliegel L (2007). Structural and functional analysis of the Na⁺/H⁺ exchanger. Biochem J401: 623–633.

SLC10 family of sodium-bile acid co-transporters

Overview: the SLC10 family transport bile acids and their derivatives in a sodium-dependent manner. Along with members of the ABC transporter family (MDR1/ABCB1; BSEP/ABCB11; and MRP2/ABCC2) and the organic solute transporter obligate heterodimer OSTα:OSTβ, these transporters allow enterohepatic circulation of bile acids (see Dawson et al., 2009; Klaassen and Aleksunes, 2010).

The SLC10 family appear to be monomeric with external N-termini and cytoplasmic C-termini and seven TM segments (Hallen et al., 1999; Banerjee and Swaan, 2006).

Systematic name	SLC10A1	SLC10A2	SLC10A6
Common abbreviation	NTCP	ASBT	SOAT
Nomenclature	Sodium/bile acid cotransporter 1	Sodium/bile acid cotransporter 2	Sodium/bile acid cotransporter 6
Ensembl ID	ENSG00000100652	ENSG00000125255	ENSG00000145283
Other names	Sodium/bile acid cotransporter, Na+/taurocholate transport protein, cell growth-inhibiting gene 29 protein	Apical sodium-dependent bile acid transporter, ileal sodium/bile acid cotransporter, ISBT, IBAT	Sodium-dependent organic anion transporter
Substrates	TUDA, TCA, TCDCA > GCA > CA (Meier et al., 1997)	GDCA > GUDCA, GCDA > TCA > CA (Craddock et al., 1998)	Estrone-3-sulphate, DHEAS (Geyer et al., 2004), TLCA, PREGS (Geyer et al., 2007)
	Thyroid hormone (Friesema et al., 1999; Visser et al., 2010)
Inhibitors	Cyclosporin, propranolol (Kim et al., 1999)	–	–
Probes	Chenodeoxycholyl-Nε-nitrobenzoxadiazol-lysine (Weinman et al., 1998)	[3H]-Taurocholate (Craddock et al., 1998)	–
Stoichiometry	2 Na+: 1 bile acid (Hagenbuch and Meier, 1996; Weinman, 1997)	>1 Na+: 1 bile acid (Craddock et al., 1998)	–

Systematic name	SLC10A3	SLC10A4	SLC10A5	SLC10A7
Common abbreviation	P3	P4	P5	P7
Nomenclature	Sodium/bile acid cotransporter 3	Sodium/bile acid cotransporter 4	Sodium/bile acid cotransporter 5	Sodium/bile acid cotransporter 7
Ensembl ID	ENSG00000126903	ENSG00000145248	ENSG00000205184	ENSG00000120519
Other names	P3 protein	–	–	C4orf13

Heterologously expressed SLC10A4 (Geyer et al., 2008) or SLC10A7 (Godoy et al., 2007) failed to exhibit significant transport of TCA, PREGS, DHEAS or choline. SLC10A4 has recently been suggested to associate with neuronal vesicles (Burger et al., 2011).

Abbreviations: CA, cholic acid; CDCA, chenodeoxycholic acid; DCA, deoxycholic acid; DHEAS, dehydroepiandrosterone sulphate; GCA, glychocholic acid; GCDA, glycochenodeoxycholic acid; GDCA, glycodeoxycholic acid; GUDCA, glycoursodeoxycholate; PREGS, pregnenolone sulphate; TCA, taurocholic acid; TCDCA, taurochenodeoxycholate; TLCA, taurolithocholic acid; TUDA, tauroursodeoxycholic acid

Further Reading

Alrefai WA, Gill RK (2007). Bile acid transporters: structure, function, regulation and pathophysiological implications. Pharm Res24: 1803–1823.

Dawson PA, Lan T, Rao A (2009). Bile acid transporters. J Lipid Res50: 2340–2357.

Geyer J, Wilke T, Petzinger E (2006). The solute carrier family SLC10: more than a family of bile acid transporters regarding function and phylogenetic relationships. Naunyn Schmiedebergs Arch Pharmacol372: 413–431.

Hagenbuch B, Dawson P (2004). The sodium bile salt cotransport family SLC10. Pflugers Arch447: 566–570.

Klaassen CD, Aleksunes LM (2010). Xenobiotic, bile acid, and cholesterol transporters: function and regulation. Pharmacol Rev62: 1–96.

Kosters A, Karpen SJ (2008). Bile acid transporters in health and disease. Xenobiotica38: 1043–1071.

SLC11 family of proton-coupled metal ion transporters

Overview: the family of proton-coupled metal ion transporters are responsible for movements of divalent cations, particularly ferrous and manganese ions, across the cell membrane (DMT1) and across endosomal (DMT1) or lysosomal/phagosomal membranes (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 it's 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. DMT1 is more widely expressed and appears to assist in divalent cation assimilation from the diet, as well as in phagocytotic cells.

Systematic name	SLC11A1	SLC11A2
Preferred abbreviation	NRAMP1	DMT1
Nomenclature		Divalent metal transporter 1
Ensembl ID	ENSG00000018280	ENSG00000110911
Other names	Natural resistance-associated macrophage protein 1	Natural resistance-associated macrophage protein 2, NRAMP2, DCT1
Endogenous substrates	Mn2+, Fe2+	Fe2+, Cd2+, Co2+, Cu2+, Mn2+
Stoichiometry	1 H+ : 1 Fe2+ (out) or 1 Fe2+ (in); 1 H+ (out)	1 H+ : 1 Fe2+ (out) (Gunshin et al., 1997)

Loss-of-function mutations in NRAMP1 are associated with increased susceptibility to microbial infection. Loss-of-function mutations in DMT1 are associated with microcytic anemia.

Further Reading

Li X, Yang Y, Zhou F, Zhang Y, Lu H, Jin Q et al. (2011). SLC11A1 (NRAMP1) polymorphisms and tuberculosis susceptibility: updated systematic review and meta-analysis. PLoS One6: e15831.

Mackenzie B, Hediger MA (2004). SLC11 family of H⁺-coupled metal-ion transporters NRAMP1 and DMT1. Pflugers Arch447: 571–579.

Nevo Y, Nelson N (2006). The NRAMP family of metal-ion transporters. Biochim Biophys Acta1763: 609–620.

SLC12 family of cation-coupled chloride transporters

Overview: the SLC12 family of chloride transporters contribute to ion fluxes across a variety of tissues. Within this family, further subfamilies are identifiable: NKCC1, NKCC2 and NCC constitute a group of therapeutically-relevant transporters, targets for loop and thiazide diuretics. These 12 TM proteins exhibit cytoplasmic termini and an extended extracellular loop at TM7/8 and are kidney-specific (NKCC2 and NCC) or show a more widespread distribution (NKCC1). A second family, the K-Cl co-transporters are also 12 TM domain proteins with cytoplasmic termini, but with an extended extracellular loop at TM 5/6. CCC6 exhibits structural similarities with the K-Cl co-transporters, while CCC9 is divergent, with 11 TM domains and a cytoplasmic N-terminus and extracellular C-terminus.

Systematic name	SLC12A1	SLC12A2	SLC12A3
Preferred abbreviation	NKCC2	NKCC1	NCC
Nomenclature	Kidney-specific Na-K-Cl symporter	Basolateral Na-K-Cl symporter	Na-Cl symporter
Ensembl ID	ENSG00000074803	ENSG00000064651	ENSG00000070915
Other names	Bumetanide-sensitive sodium-(potassium)-chloride cotransporter 2, BSC2	Bumetanide-sensitive sodium-(potassium)-chloride cotransporter 1, BSC1	Thiazide-sensitive sodium-chloride cotransporter, TSC
Inhibitors	Bumetanide, piretanide, frusemide (Hannaert et al., 2002)	Bumetanide, piretanide, frusemide (Hannaert et al., 2002)	Hydrochlorothiazide, chlorothiazide, metolazone
Stoichiometry	1 Na+ : 1 K+ : 2 Cl- (in)	1 Na+ : 1 K+ : 2 Cl- (in)	1 Na+ : 1 Cl- (in)

Systematic name	SLC12A4	SLC12A5	SLC12A6	SLC12A7
Preferred abbreviation	KCC1	KCC2	KCC3	KCC4
Nomenclature	K-Cl cotransporter 1	K-Cl cotransporter 2	K-Cl cotransporter 3	K-Cl cotransporter 4
Ensembl ID	ENSG00000124067	ENSG00000124140	ENSG00000140199	ENSG00000113504
Other names	Electroneutral potassium-chloride cotransporter 1, erythroid K-Cl cotransporter 1	Electroneutral potassium-chloride cotransporter 2, erythroid K-Cl cotransporter 2	Electroneutral potassium-chloride cotransporter 3	Electroneutral potassium-chloride cotransporter 4
Inhibitors	DIOA	VU0240551 (Delpire et al., 2009), DIOA	DIOA	DIOA
Stoichiometry	1 K+ : 1 Cl- (out)	1 K+ : 1 Cl- (out)	1 K+ : 1 Cl- (out)	1 K+ : 1 Cl- (out)

Systematic name	SLC12A8	SLC12A9
Preferred abbreviation	CCC9	CCC6
Nomenclature	Cation-chloride cotransporter 9	Cation-chloride cotransporter 6
Ensembl ID	ENSG00000221955	ENSG00000146828
Other names	–	Potassium-chloride transporter 9, CCC-interacting protein 1
Substrates	Spermine, spermidine, glutamate, aspartate (Daigle et al., 2009)	–
Stoichiometry	Unknown	–

CCC6 is regarded as an orphan transporter.

DIOA is able to differentiate KCC isoforms from NKCC and NCC transporters, but also inhibits CFTR (Ito et al., 2001).

Abbreviations: DIOA, 2-[(2-butyl-6,7-dichloro-2-cyclopentyl-1-oxo-3H-inden-5-yl)oxy]acetic acid; VU0240551, N-(4-methyl-1,3-thiazol-2-yl)-2-(6-phenylpyridazin-3-yl)sulfanylacetamide

Further Reading

Castrop H, Schnermann J (2008). Isoforms of renal Na-K-2Cl cotransporter NKCC2: expression and functional significance. Am J Physiol Renal Physiol295: F859–F866.

Gamba G, Friedman PA (2009). Thick ascending limb: the Na⁺:K⁺:2Cl^- co-transporter, NKCC2, and the calcium-sensing receptor, CaSR. Pflugers Arch458: 61–76.

Hebert SC, Mount DB, Gamba G (2004). Molecular physiology of cation-coupled Cl^- cotransport: the SLC12 family. Pflugers Arch447: 580–593.

Kahle KT, Staley KJ, Nahed BV, Gamba G, Hebert SC, Lifton RP et al. (2008). Roles of the cation-chloride cotransporters in neurological disease. Nat Clin Pract Neurol4: 490–503.

Kahle KT, Rinehart J, Lifton RP (2010). Phosphoregulation of the Na-K-2Cl and K-Cl cotransporters by the WNK kinases. Biochim Biophys Acta1802: 1150–1158.

Lang F, Vallon V, Knipper M, Wangemann P (2007). Functional significance of channels and transporters expressed in the inner ear and kidney. Am J Physiol Cell Physiol293: C1187–C1208.

Lionetto MG, Schettino T (2006). The Na⁺-K⁺-2Cl^- cotransporter and the osmotic stress response in a model salt transport epithelium. Acta Physiol (Oxf)187: 115–124.

Wagner CA, Devuyst O, Bourgeois S, Mohebbi N (2009). Regulated acid-base transport in the collecting duct. Pflugers Arch458: 137–156.

SLC13 family of sodium-dependent sulphate/carboxylate transporters

Overview: within the SLC13 family, two groups of transporters may be differentiated on the basis of the substrates transported: NaS1 and NaS2 convey sulphate, while NaC1-3 transport carboxylates. NaS1 and NaS2 transporters are made up of 13 TM domains, with an intracellular N terminus and are electrogenic with physiological roles in the intestine, kidney and placenta. NaC1, NaC2 and NaC3 are made up of 11 TM domains with an intracellular N terminus and are electrogenic, with physiological roles in the kidney and liver.

Systematic name	SLC13A1	SLC13A2	SLC13A3
Preferred abbreviation	NaS1	NaC1	NaC3
Nomenclature	Na+/sulfate cotransporter	Na+/dicarboxylate cotransporter 1	Na+/dicarboxylate cotransporter 3
Other names	Renal sodium/sulfate cotransporter, NaSi-1	Renal sodium/dicarboxylate cotransporter, NaDC1	Sodium-dependent high-affinity dicarboxylate transporter 2, NaDC3
Ensembl ID	ENSG00000081800	ENSG00000007216	ENSG00000158296
Endogenous substrates	Sulphate, thiosulphate, selenate	Succinate, citrate	Succinate, citrate
Stoichiometry	3 Na+ : 1 SO42− (in)	3 Na+ : 1 dicarboxylate2− (in)	Unknown

Systematic name	SLC13A4	SLC13A5
Preferred abbreviation	NaS2	NaC2
Nomenclature	Na+/sulfate cotransporter	Na+/citrate cotransporter
Other names	SUT1	Sodium-coupled citrate transporter, sodium-dependent citrate transporter, NaCT
Ensembl ID	ENSG00000164707	ENSG00000141485
Endogenous substrates	Sulphate	Citrate, pyruvate
Stoichiometry	3 Na+ : SO42− (in)	Unknown

Further Reading

Lee A, Dawson PA, Markovich D (2005). NaSi-1 and Sat-1: structure, function and transcriptional regulation of two genes encoding renal proximal tubular sulfate transporters. Int J Biochem Cell Biol37: 1350–1356.

Markovich D (2011). Physiological roles of renal anion transporters NaS1 and Sat1. Am J Physiol Renal Physiol300: F1267–F1270.

Markovich D, Murer H (2004). The SLC13 gene family of sodium sulphate/carboxylate cotransporters. Pflugers Arch447: 594–602.

Markovich D, Aronson PS (2007). Specificity and regulation of renal sulfate transporters. Annu Rev Physiol69: 361–375.

SLC14 family of facilitative urea transporters

Overview: as a product of protein catabolism, urea is moved around the body and through the kidneys for excretion. Although there is experimental evidence for concentrative urea transporters, these have not been defined at the molecular level. The SLC14 family are facilitative transporters, allowing urea movement down it's 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 (see Stewart, 2011). Topographical modelling suggests that the majority of the variants of SLC14 transporters have 10 TM domains, with a glycosylated extracellular loop at TM5/6, and intracellular C- and N-termini. The UT-A1 splice variant, exceptionally, has 20 TM domains, equivalent to a combination of the UT-A2 and UT-A3 splice variants.

Systematic name	SLC14A1	SLC14A2
Preferred abbreviation	UT-B	UT-A
Nomenclature	Erythrocyte urea transporter	Kidney urea transporter
Ensembl ID	ENSG00000141469	ENSG00000132874
Other names	UTB1	UTA1
Endogenous substrates	Urea, formamide, ammonium carbonate (Zhao et al., 2007)	Urea (Maciver et al., 2008)
Synthetic substrates	Acetamide, methylurea, methylformamide, acrylamide (Zhao et al., 2007)	–
Stoichiometry	Equilibrative	Equilibrative

Further Reading

Bagnasco SM (2005). Role and regulation of urea transporters. Pflugers Arch450: 217–226.

Bagnasco SM (2006). The erythrocyte urea transporter UT-B. J Membr Biol212: 133–138.

Fenton RA (2009). Essential role of vasopressin-regulated urea transport processes in the mammalian kidney. Pflugers Arch458: 169–177.

Shayakul C, Hediger MA (2004). The SLC14 gene family of urea transporters. Pflugers Arch447: 603–609.

Smith CP (2009). Mammalian urea transporters. Exp Physiol94: 180–185.

Smith CP, Fenton RA (2006). Genomic organization of the mammalian SLC14a2 urea transporter genes. J Membr Biol212: 109–117.

Stewart G (2011). The emerging physiological roles of the SLC14A family of urea transporters. Br J Pharmacol in press.

Yang B, Bankir L (2005). Urea and urine concentrating ability: new insights from studies in mice. Am J Physiol Renal Physiol288: F881–F896.

SLC15 family of peptide transporters

Overview: the SLC15 family of peptide transporters may be divided on the basis of structural and functional differences into two subfamilies: SLC15A1 (PepT1) and SLC15A2 (PepT2) transport di- and tripeptides, but not amino acids, whereas SLC15A3 (PHT2) and SLC15A4 (PHT1) transport histidine and some di- and tripeptides (see Daniel and Kottra, 2004). The transporters are 12 TM proteins with intracellular termini and an extended extracellular loop at TM 9/10. The crystal structure of PepT_So (a prokaryote homologue of PepT1 and PepT2 from Shewanella oneidensis) confirms many of the predicted structural features of mammalian PepT1 and PepT2 (Newstead et al., 2011).

PHT1 has been suggested to be intracellular (Romano et al., 2010), while PHT2 protein is located on lysosomes in transfected cells (Botka et al., 2000; Sakata et al., 2001; Herrera-Ruiz and Knipp, 2003). PHT1 is hypothesised to mediate efflux of bacterial-derived peptides into the cytosol perhaps in the colon where SLC15A4 mRNA expression is increased in inflammatory bowel disease (Lee et al., 2009). Transport via PHT1 may be important in immune responses as both Toll-like receptor- and NOD1-mediated responses are reduced in PHT1 knockout mice or mouse strains expressing mutations in PHT1 (Blasius et al., 2010; Sasawatari et al., 2011).

Systematic name	SLC15A1	SLC15A2	SLC15A3	SLC15A4
Preferred abbreviation	PepT1	PepT2	PHT2	PHT1
Nomenclature	Peptide transporter 1	Peptide transporter 2	Peptide transporter 3	Peptide transporter 4
Ensembl ID	ENSG00000088386	ENSG00000163406	ENSG00000110446	ENSG00000139370
Other names	Intestinal H+/peptide cotransporter, low affinity peptide transporter	Kidney H+/peptide cotransporter, high affinity peptide transporter	Peptide/histidine transporter 2, osteoclast transporter, peptide transporter 3, PTR3, cAMP-inducible 1 protein	Peptide/histidine transporter 1, peptide transporter 4, PTR4
Endogenous substrates	Dipeptides, tripeptides, 5-aminolevulinic acid (Doring et al., 1998)	Dipeptides, tripeptides, 5-aminolevulinic acid	Dipeptides, tripeptides, histidine, carnosine	Dipeptides, tripeptides, histidine, carnosine
Synthetic substrates	Cyclacillin, cefadroxil (Ganapathy et al., 1995), enalapril, captopril (Temple and Boyd, 1998), muramyl dipeptide (Vavricka et al., 2004), fMLP (Merlin et al., 1998)	Cyclacillin, cefadroxil (Ganapathy et al., 1995)	–	Valacyclovir (Bhardwaj et al., 2006)
Inhibitors	Lys[Z(NO2)]-Pro (Knutter et al., 2001), 4-AMBA (Darcel et al., 2005)	Lys[Z(NO2)]-Pro, Lys[Z(NO2)]-Lys[Z(NO2)] (Theis et al., 2002; Biegel et al., 2006)
Probes	[3H]-, [11C]- or [14C]-GlySar	[3H]-, [11C]- or [14C]-GlySar	[3H]-or [14C]-Histidine	[3H]-or [14C]-Histidine
Stoichiometry	2 H+ : 1 zwitterionic peptide (in)	2 H+ : 1 zwitterionic peptide (in)	Unknown	Unknown

The PepT1 and PepT2 transporters are particularly promiscuous in the transport of dipeptides and tripeptides of any sequence from the endogenous amino acids, as well as some d-amino acid containing peptides. PepT1 has also been exploited to allow delivery of therapeutic pro-drugs, such as those for zidovudine (Han et al., 1998), sulpiride (Watanabe et al., 2002) and cytarabine (Sun et al., 2009).

d-Ala-Lys-AMCA has been used as a fluorescent probe to identify transport via both PepT1 and PepT2 (Rubio-Aliaga and Daniel, 2008).

Abbreviations: d-Ala-Lys-AMCA, d-Ala-Lys-N^ε-7-amino-4-methyl-coumarin-3-acetic acid; 4-AMBA, 4-(aminomethyl)benzoic acid; fMLP, formyl-Met-Leu-Phe

Further Reading

Anderson CMH, Thwaites DT (2010). Hijacking solute carriers for proton-coupled drug transport. Physiology25: 364–377.

Biegel A, Knutter I, Hartrodt B, Gebauer S, Theis S, Luckner P et al. (2006). The renal type H⁺/peptide symporter PEPT2: structure-affinity relationships. Amino Acids31: 137–156.

Brandsch M (2009). Transport of drugs by proton-coupled peptide transporters: pearls and pitfalls. Expert Opin Drug Metab Toxicol5: 887–905.

Brandsch M, Knutter I, Leibach FH (2004). The intestinal H⁺/peptide symporter PEPT1: structure-affinity relationships. Eur J Pharm Sci21: 53–60.

Charrier L, Merlin D (2006). The oligopeptide transporter hPepT1: gateway to the innate immune response. Lab Invest86: 538–546.

Daniel H (2004). Molecular and integrative physiology of intestinal peptide transport. Annu Rev Physiol66: 361–384.

Daniel H, Kottra G (2004). The proton oligopeptide cotransporter family SLC15 in physiology and pharmacology. Pflügers Arch447: 610–618.

Kamal MA, Keep RF, Smith DE (2008). Role and relevance of PEPT2 in drug disposition, dynamics, and toxicity. Drug Metab Pharmacokinet23: 236–242.

Meredith D, Price RA (2006). Molecular modeling of PepT1–towards a structure. J Membr Biol213: 79–88.

Rubio-Aliaga I, Daniel H (2008). Peptide transporters and their roles in physiological processes and drug disposition. Xenobiotica38: 1022–1042.

Terada T, Inui K (2007). Gene expression and regulation of drug transporters in the intestine and kidney. Biochem Pharmacol73: 440–449.

Thwaites DT, Anderson CMH (2007). H⁺-coupled nutrient, micronutrient and drug transporters in the mammalian small intestine. Exp Physiol92: 603–619.

SLC16 family of monocarboxylate transporters

Overview: members of the SLC16 family may be divided into subfamilies on the basis of substrate selectivities, particularly lactate, pyruvate and ketone bodies, as well as aromatic amino acids. Topology modelling suggests 12 TM domains, with intracellular termini and an extended loop at TM 6/7.

The proton-coupled monocarboxylate transporters allow transport of the products of cellular metabolism, principally lactate and pyruvate.

Systematic name	SLC16A1	SLC16A3	SLC16A7	SLC16A8
Preferred abbreviation	MCT1	MCT4	MCT2	MCT3
Nomenclature	Monocarboxylate transporter 1	Monocarboxylate transporter 4	Monocarboxylate transporter 2	Monocarboxylate transporter 3
Ensembl ID	ENSG00000155380	ENSG00000141526	ENSG00000118596	ENSG00000100156
Other names	–	Monocarboxylate transporter 3, MCT 3	–	REMP
Endogenous substrates	Lactate, pyruvate, β-hydroxybutyrate	Lactate, pyruvate	Lactate, pyruvate	Lactate
Synthetic substrates	GHB (Wang et al., 2006)	–	–	–
Stoichiometry	1 H+ : 1 monocarboxylate- (out)	1 H+ : 1 monocarboxylate- (out)	1 H+ : 1 monocarboxylate- (out)	1 H+ : 1 monocarboxylate- (out)

MCT1 and MCT2, but not MCT3 and MCT4, are inhibited by CHC, which also inhibits members of the mitochondrial transporter family, SLC25 (see Page S256).

Systematic name	SLC16A2	SLC16A10
Preferred abbreviation	MCT8	TAT1
Nomenclature	Monocarboxylate transporter 8	Monocarboxylate transporter 10
Ensembl ID	ENSG00000147100	ENSG00000112394
Other names	Monocarboxylate transporter 7, MCT 7, X-linked PEST-containing transporter	T-type amino acid transporter 1, aromatic amino acid transporter 1, MCT10
Endogenous substrates	T3, T4 (Friesema et al., 2006)	L-Tryptophan, L-phenylalanine, L-tyrosine, L-DOPA
Stoichiometry	Unknown	Unknown

Systematic name	SLC16A4	SLC16A5	SLC16A6	SLC16A9
Preferred abbreviation	MCT5	MCT6	MCT7	MCT9
Nomenclature	Monocarboxylate transporter 5	Monocarboxylate transporter 6	Monocarboxylate transporter 7	Monocarboxylate transporter 9
Ensembl ID	ENSG00000168679	ENSG00000170190	ENSG00000108932	ENSG00000165449
Other names	Monocarboxylate transporter 4, MCT 4	Monocarboxylate transporter 5, MCT 5	Monocarboxylate transporter 6, MCT 6	–
Stoichiometry	Unknown	Unknown	Unknown	Unknown

MCT6 has been reported to transport bumetamide, but not short chain fatty acids (Murakami et al., 2005).

Systematic name	SLC16A11	SLC16A12	SLC16A13	SLC16A14
Preferred abbreviation	MCT11	MCT12	MCT13	MCT14
Nomenclature	Monocarboxylate transporter 11	Monocarboxylate transporter 12	Monocarboxylate transporter 13	Monocarboxylate transporter 14
Ensembl ID	ENSG00000174326	ENSG00000152779	ENSG00000174327	ENSG00000163053
Stoichiometry	Unknown	Unknown	Unknown	Unknown

MCT5-MCT7, MCT9 and MCT11-14 are regarded as orphan transporters.

Abbreviations: CHC, (E)-2-cyano-3-(4-hydroxyphenyl)prop-2-enoic acid; GHB, gamma-hydroxybutyrate; T3, (2S)-2-amino-3-[4-(4-hydroxy-3-iodophenoxy)-3,5-diiodophenyl]propanoic acid, also known as triiodothyronine; T4, thyroxine

Further Reading

Anderson CM, Thwaites DT (2010). Hijacking solute carriers for proton-coupled drug transport. Physiology (Bethesda)25: 364–377.

Braun D, Wirth EK, Schweizer U (2010). Thyroid hormone transporters in the brain. Rev Neurosci21: 173–186.

van der Deure WM, Peeters RP, Visser TJ (2010). Molecular aspects of thyroid hormone transporters, including MCT8, MCT10, and OATPs, and the effects of genetic variation in these transporters. J Mol Endocrinol44: 1–11.

Friesema EC, Visser WE, Visser TJ (2010). Genetics and phenomics of thyroid hormone transport by MCT8. Mol Cell Endocrinol322: 107–113.

Halestrap AP, Meredith D (2004). The SLC16 gene family-from monocarboxylate transporters (MCTs) to aromatic amino acid transporters and beyond. Pflugers Arch447: 619–628.

Heuer H, Visser TJ (2009). Pathophysiological importance of thyroid hormone transporters. Endocrinology150: 1078–1083.

Jansen J, Friesema EC, Milici C, Visser TJ (2005). Thyroid hormone transporters in health and disease. Thyroid15: 757–768.

Meredith D, Christian HC (2008). The SLC16 monocaboxylate transporter family. Xenobiotica38: 1072–1106.

Morris ME, Felmlee MA (2008). Overview of the proton-coupled MCT (SLC16A) family of transporters: characterization, function and role in the transport of the drug of abuse γ-hydroxybutyric acid. AAPS J10: 311–321.

Visser TJ (2007). Thyroid hormone transporters. Horm Res68 (Suppl. 5): 28–30.

Visser WE, Friesema EC, Jansen J, Visser TJ (2008). Thyroid hormone transport in and out of cells. Trends Endocrinol Metab19: 50–56.

SLC17 phosphate and organic anion transporter family

Overview: The SLC17 family are sometimes referred to as Type I sodium-phosphate co-transporters, alongside Type II (SLC34 family, see Page S265) and Type III (SLC20 family, see Page S251) transporters. Within the SLC17 family, however, further subgroups of organic anion transporters may be defined, allowing the accumulation of sialic acid in the endoplasmic reticulum and glutamate or nucleotides in synaptic and secretory vesicles. Topology modelling suggests 12 TM domains.

Type I sodium-phosphate co-transporters are expressed in the kidney and intestine

Systematic name	SLC17A1	SLC17A2	SLC17A3	SLC17A4
Preferred abbreviation	NPT1	NPT3	NPT4	–
Nomenclature	Sodium/phosphate cotransporter 1	Sodium/phosphate cotransporter 3	Sodium/phosphate cotransporter 4	–
Ensembl ID	ENSG00000124568	ENSG00000112337	ENSG00000124564	ENSG00000146039
Other names	NaPi-1, renal sodium-dependent phosphate transport protein 1	–	–	Putative small intestine sodium-dependent phosphate transport protein
Substrates	Phosphate, organic acids, chloride, urate (Iharada et al., 2010)	–	–	–
Synthetic substrates	Probenecid, penicillin (Busch et al., 1996)	–	–
Stoichiometry	Unknown	Unknown	Unknown	Unknown

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 (Miyaji et al., 2011), driven by proton gradients. In lysosomes, degradation of glycoproteins generates amino acids and sugar residues, which are metabolized further following export from the lysosome.

Systematic name	SLC17A5
Preferred abbreviation	AST
Nomenclature	Sialin
Ensembl ID	ENSG00000119899
Other names	Sodium/sialic acid cotransporter, membrane glycoprotein HP59
Endogenous substrates	Sialic acid, lactate, glucuronic acid, gluconate (out)
	Aspartate, glutamate (in) (Miyaji et al., 2011)
Stoichiometry	1 H+ : 1 sialic acid (out)

Loss-of-function mutations in sialin are associated with Salla disease, an autosomal recessive neurodegenerative disorder associated with sialic acid storage disease (Verheijen et al., 1999).

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 (Bellocchio et al., 2000).

Systematic name	SLC17A7	SLC17A6	SLC17A8
Preferred abbreviation	VGLUT1	VGLUT2	VGLUT3
Nomenclature	Vesicular glutamate transporter 1	Vesicular glutamate transporter 2	Vesicular glutamate transporter 3
Ensembl ID	ENSG00000104888	ENSG00000091664	ENSG00000179520
Other names	Brain-specific Na+-dependent inorganic phosphate cotransporter, BNPI	Differentiation-associated Na+-dependent inorganic phosphate cotransporter, differentiation-associated BNPI	–
Endogenous substrates	L-glutamate > D-glutamate	L-glutamate > D-glutamate	L-glutamate > D-glutamate
Stoichiometry	Unknown	Unknown	Unknown

Endogenous ketoacids produced during fasting have been proposed to regulate VGLUT function through blocking chloride ion-mediated allosteric enhancement of transporter function (Juge et al., 2010).

The vesicular nucleotide transporter is the most recent member of the SLC17 family to have an assigned function. Uptake of ATP was independent of pH, but dependent on chloride ions and membrane potential (Sawada et al., 2008).

Systematic name	SLC17A9
Preferred abbreviation	VNUT
Nomenclature	Vesicular nucleotide transporter
Ensembl ID	ENSG00000101194
Other names	Uncharacterized MFS-type transporter C20orf59
Endogenous substrates	ATP, GTP, GDP (Sawada et al., 2008)
Stoichiometry	Unknown

VGLUTs and VNUT can be inhibited by DIDS and Evans blue dye.

Abbreviations: DIDS, 5-isothiocyanato-2-[(E)-2-(4-isothiocyanato-2-sulfophenyl)ethenyl]benzenesulfonic acid

Further Reading

El Mestikawy S, Wallen-Mackenzie A, Fortin GM, Descarries L, Trudeau LE (2011). From glutamate co-release to vesicular synergy: vesicular glutamate transporters. Nat Rev Neurosci12: 204–216.

Erickson JD, De GS, Varoqui H, Schafer MK, Weihe E (2006). Activity-dependent regulation of vesicular glutamate and GABA transporters: a means to scale quantal size. Neurochem Int48: 643–649.

Fei H, Grygoruk A, Brooks ES, Chen A, Krantz DE (2008). Trafficking of vesicular neurotransmitter transporters. Traffic9: 1425–1436.

Moriyama Y, Omote H (2008). Vesicular glutamate transporter acts as a metabolic regulator. Biol Pharm Bull31: 1844–1846.

Omote H, Miyaji T, Juge N, Moriyama Y (2011). Vesicular neurotransmitter transporter: bioenergetics and regulation of glutamate transport. Biochemistry50: 5558–5565.

Reimer RJ, Edwards RH (2004). Organic anion transport is the primary function of the SLC17/type I phosphate transporter family. Pflugers Arch447: 629–635.

Santos MS, Li H, Voglmaier SM (2009). Synaptic vesicle protein trafficking at the glutamate synapse. Neuroscience158: 189–203.

Shigeri Y, Seal RP, Shimamoto K (2004). Molecular pharmacology of glutamate transporters, EAATs and VGLUTs. Brain Res Brain Res Rev45: 250–265.

SLC18 family of vesicular amine transporters

Overview: The vesicular amine transporters (VATs) are putative 12 TM domain proteins that function to transport singly positively charged amine neurotransmitters and hormones from the cytoplasm and concentrate them within secretory vesicles. They function as amine/proton antiporters driven by secondary active transport utilizing the proton gradient established by a multi-subunit vacuolar ATPase (see Page S218) that acidifies secretory vesicles (reviewed by Eiden et al., 2004). The vesicular acetylcholine transporter (VAChT; Erickson et al., 1994) localizes to cholinergic neurons, but non-neuronal expression has also been claimed (Schirmer et al., 2011). Vesicular monoamine transporter 1 (VMAT1, Erickson and Eiden, 1993) is mainly expressed in peripheral neuroendocrine cells, but most likely not in the CNS, whereas VMAT2 (Erickson et al., 1996) distributes between both central and peripheral sympathetic monoaminergic neurones (Eiden and Weihe, 2011).

Common abbreviation	VMAT1	VMAT2	VAChT
Systematic name	SLC18A1	SLC18A2	SLC18A3
Nomenclature	Vesicular monoamine transporter 1	Vesicular monoamine transporter 2	Vesicular acetylcholine transporter
Other names	Chromaffin granule amine transporter (CGAT), VAT1, MAT	Synaptic vesicular amine transporter (SVAT), SVMT, VAT2	(VAChT)
Ensembl ID	ENSG00000036565	ENSG00000165646	ENSG00000187714
Endogenous substrates (pKM/pKi)	5-HT (5.8), dopamine (5.4), adrenaline (5.3), noradrenaline (4.9), histamine (2.3) (Erickson et al., 1996)	5-HT (6.0), dopamine (5.9), adrenaline (5.7), noradrenaline (5.5), histamine (3.8) (Erickson et al., 1996)	Acetylcholine (3.1), choline (2.3) (Bravo et al., 2004; Khare et al., 2010)
Synthetic substrates (pKM/pKi)	Fenfluramine (5.5), MDMA (4.7), D-am-phetamine (4.3), MPP+ (4.2), phenyl-ethylamine (4.5) (Erickson et al., 1996)	D-amphetamine (5.7), phenyethylamine (5.4), fenfluramine (5.3), MDMA (5.2), MPP+ (5.1) (Erickson et al., 1996)	TPP+, N-methyl-pyridinium-2-aldoxime, N-(4′-pentanonyl)-4-(4″-dimethylamino-styryl)pyridinium, ethididium (Bravo et al., 2005)
Inhibitors (pKi)	Reserpine (7.45), ketanserin (5.8), TBZ (>4.7) (Erickson et al., 1996)	Reserpine (7.9), TBZ (7.0), ketanserin (6.3) (Erickson et al., 1996)	Vesamicol (8.7), aminobenzovesamicol (10.9), (Efange et al., 1995)
Probes (Kd)		[3H]-TBZOH (6.6 nM, Varoqui and Erickson, 1996), [125I]-iodovinyl-TBZ (8.2 nM, Kung et al., 1994); [125I]-8-azido-3-iodoketanserine (photoaffinity ligand), [11C]-DTBZ (PET ligand)	[3H]-vesamicol (4.1 nM, Varoqui and Erickson, 1996), [123I]-iodobenzovesamicol (SPECT ligand)
Stoichiometry	1 amine (in): 2H+ (out)	1 amine (in): 2H+ (out)	1 amine (in): 2H+ (out)

pKi values for endogenous and synthetic substrate inhibitors of human VMAT1 and VMAT2 are for inhibition of [³H]-5-HT uptake in transfected and permeabilised CV-1 cells as detailed by Erickson et al. (1996). In addition to the monoamines listed in the table, the trace amines tyramine and phenylethylamine are probable substrates for VMAT2 (Eiden and Weihe, 2011). Probes listed in the table are those currently employed; additional agents have been synthesized (e.g.Zhu et al., 2009).

Abbreviations: DTBZ, dihydrotetrabenazine; MDMA, 3,4-methylenedioxymethamphetamine; MPP⁺, 1-methyl-4-phenylpyridinium; TBZ, tetrabenazine; TBZOH, α-[O-methyl-³H]dihydrotetrabenazine; TPP⁺, tetraphenylphosphonium

Further Reading

Chaudhry FA, Edwards RH, Fonnum F (2008). Vesicular neurotransmitter transporters as targets for endogenous and exogenous toxic substances. Annu Rev Pharmacol Toxicol48: 277–301.

Eiden LE, Weihe E (2011). VMAT2: a dynamic regulator of brain monoaminergic neuronal function interacting with drugs of abuse. Ann N Y Acad Sci1216: 86–98.

Eiden LE, Schafer MK, Weihe E, Schutz B (2004). The vesicular amine transporter family (SLC18): amine/proton antiporters required for vesicular accumulation and regulated exocytotic secretion of monoamines and acetylcholine. Pflugers Arch447: 636–640.

Fei H, Grygoruk A, Brooks ES, Chen A, Krantz DE (2008). Trafficking of vesicular neurotransmitter transporters. Traffic9: 1425–1436.

Fleckenstein AE, Volz TJ, Riddle EL, Gibb JW, Hanson GR (2007). New insights into the mechanism of action of amphetamines. Annu Rev Pharmacol Toxicol47: 681–698.

Fleckenstein AE, Volz TJ, Hanson GR (2009). Psychostimulant-induced alterations in vesicular monoamine transporter-2 function: neurotoxic and therapeutic implications. Neuropharmacology56 (Suppl. 1): 133–138.

Giboureau N, Som IM, Boucher-Arnold A, Guilloteau D, Kassiou M (2010). PET Radioligands for the Vesicular Acetylcholine Transporter (VAChT). Curr Top Med Chem10: 1569–1583.

Guillot TS, Miller GW (2009). Protective actions of the vesicular monoamine transporter 2 (VMAT2) in monoaminergic neurons. Mol Neurobiol39: 149–170.

Khare P, White AR, Mulakaluri A, Parsons SM (2010). Equilibrium binding and transport by vesicular acetylcholine transporter. Methods Mol Biol637: 181–219.

Parsons SM (2000). Transport mechanisms in acetylcholine and monoamine storage. FASEB J14: 2423–2434.

Schuldiner S, Shirvan A, Linial M (1995). Vesicular neurotransmitter transporters: from bacteria to humans. Physiol Rev75: 369–392.

Van der Kloot W (2003). Loading and recycling of synaptic vesicles in the Torpedo electric organ and the vertebrate neuromuscular junction. Prog Neurobiol71: 269–303.

Zheng G, Dwoskin LP, Crooks PA (2006). Vesicular monoamine transporter 2: role as a novel target for drug development. AAPS J8: E682–E692.

SLC19 family of vitamin transporters

Overview: the B vitamins folate and thiamine are transported across the cell membrane, particularly in the intestine, kidneys and placenta, using pH differences as driving forces. Topological modelling suggests the transporters have 12 TM domains.

Systematic name	SLC19A1	SLC19A2	SLC19A3
Nomenclature	Folate transporter 1	Thiamine transporter 1	Thiamine transporter 2
Common abbreviation	FOLT	ThTr1	ThTr2
Ensembl ID	ENSG00000173638	ENSG00000117479	ENSG00000135917
Other names	Reduced folate carrier protein, RFC1, intestinal folate carrier, IFC1, placental folate transporter	Thiamine carrier 1, TC1
Endogenous substrates	Tetrahydrofolate, N5-methylfolate, folate (Prasad et al., 1995), thiamine monophosphate (Zhao et al., 2002)	Thiamine	Thiamine
Synthetic substrates	Methotrexate, folinic acid	–	–
Probes	[3H]-Folate, [3H]-methotrexate (Assaraf et al., 1998)	[3H]-Thiamine (Dutta et al., 1999)	[3H]-Thiamine (Rajgopal et al., 2001)
Stoichiometry	1 Folate (in) : 1 OH- (out)	1 Thiamine (in) : 1 H+ (out)	1 Thiamine (in) : 1 H+ (out)

Loss-of-function mutations in ThTr1 underlie thiamine-responsive megaloblastic anemia syndrome (Diaz et al., 1999).

Further Reading

Ganapathy V, Smith SB, Prasad PD (2004). SLC19: the folate/thiamine transporter family. Pflugers Arch447: 641–646.

Yuasa H, Inoue K, Hayashi Y (2009). Molecular and functional characteristics of proton-coupled folate transporter. J Pharm Sci98: 1608–1616.

SLC20 family of sodium-dependent phosphate transporters

Overview: the SLC20 family is looked upon not only as ion transporters, but also as retroviral receptors. As ion transporters, they are sometimes referred to as Type III sodium-phosphate co-transporters, alongside Type I (SLC17 family, see Page S247) and Type II (SLC34 family, see Page S265). PiTs are cell-surface transporters, composed of ten TM domains with cytoplasmic C- and N-termini. PiT1 is a focus for dietary phosphate and vitamin D (see Page S188) regulation of parathyroid hormone secretion from the parathyroid gland. PiT2 appears to be involved in intestinal absorption of dietary phosphate.

Systematic name	SLC20A1	SLC20A2
Preferred abbreviation	PiT1	PiT2
Nomenclature	Sodium-dependent phosphate transporter 1	Sodium-dependent phosphate transporter 2
Ensembl ID	ENSG00000144136	ENSG00000168575
Other names	Gibbon ape leukemia virus receptor 1, GLVR-1	Gibbon ape leukemia virus receptor 2, GLVR-2
Substrates	Phosphate, arsenate (Ravera et al., 2007)	Phosphate (Ravera et al., 2007)
Stoichiometry	>1 Na+ : 1 HPO42− (in)	>1 Na+ : 1 HPO42− (in)

Further Reading

Collins JF, Bai L, Ghishan FK (2004). The SLC20 family of proteins: dual functions as sodium-phosphate cotransporters and viral receptors. Pflugers Arch447: 647–652.

Virkki LV, Biber J, Murer H, Forster IC (2007). Phosphate transporters: a tale of two solute carrier families. Am J Physiol Renal Physiol293: F643–F654.

SLC22 family of organic cation and anion transporters

Overview: the SLC22 family of transporters is mostly composed of non-selective transporters, which are expressed highly in liver, kidney and intestine, playing a major role in drug disposition. The family may be divided into three subfamilies based on the nature of the substrate transported: organic cations (OCTs), organic anions (OATs) and organic zwiterrion/cations (OCTN). Membrane topology is predicted to contain 12 TM domains with intracellular termini, and an extended extracellular loop at TM 1/2.

Organic cation transporters (OCT) are electrogenic, Na⁺-independent and reversible.

Systematic name	SLC22A1	SLC22A2	SLC22A3
Preferred abbreviation	OCT1	OCT2	OCT3
Nomenclature	Organic cation transporter 1	Organic cation transporter 2	Organic cation transporter 3
Ensembl ID	ENSG00000175003	ENSG00000112499	ENSG00000146477
Other names	–	–	Extraneuronal monoamine transporter, EMT
Endogenous substrates	Choline, 5HT, PGE2, PGF2α	Dopamine, histamine (Grundemann et al., 1999), PGE2 (Kimura et al., 2002)	5HT, noradrenaline, dopamine (Zhu et al., 2010)
Synthetic substrates	TEA, MPP, desipramine, acyclovir, metformin	MPP, TEA, d-tubocurarine, pancuronium (Gorboulev et al., 1997)	MPP, TEA, quinidine
Stoichiometry	Unknown	Unknown	Unknown

Corticosterone and quinine are able to inhibit all three organic cation transporters.

Organic zwitterion/cation transporters (OCTN) function as organic cation uniporters, organic cation/proton exchangers or sodium/carnitine co-transporters.

Systematic name	SLC22A4	SLC22A5	SLC22A16
Preferred abbreviation	OCTN1	OCTN2	CT2
Nomenclature	Organic cation/carnitine transporter 1	Organic cation/carnitine transporter 2	Carnitine transporter 2
Ensembl ID	ENSG00000197208	ENSG00000197375	ENSG00000004809
Other names	Ergothioneine transporter, ET	High-affinity sodium-dependent carnitine cotransporter, CT1	Organic cation/carnitine transporter 6, OCT6, organic cation transporter OKB1, Fly-like putative transporter 2, Flipt 2
Endogenous substrates	L-Carnitine	L-Carnitine, acetyl-L-carnitine	L-Carnitine
Synthetic substrates	TEA, MPP, mepyramine, verapamil	TEA, MPP, mepyramine, verapamil	–
Stoichiometry	Unknown	Unknown	Unknown

Organic anion transporters (OATs) are non-selective transporters prominent in the kidney and intestine.

Systematic name	SLC22A6	SLC22A7	SLC22A8	SLC22A9	SLC22A10	SLC22A11
Preferred abbreviation	OAT1	OAT2	OAT3	OAT4	OAT5
Nomenclature	Organic anion transporter 1	Organic anion transporter 2	Organic anion transporter 3	Organic anion transporter 4	Organic anion transporter 5	Organic anion transporter 4
Ensembl ID	ENSG00000197901	ENSG00000137204	ENSG00000149452	ENSG00000149742	ENSG00000184999	ENSG00000168065
Other names	Renal organic anion transporter 1, hROAT1, PAH transporter, hPAHT	Novel liver transporter	–	UST3	–	OAT4
Synthetic substrates	PAH, non-steroidal anti-inflammatory drugs	PAH, PGE2, non-steroidal anti-inflammatory drugs	PAH, ochratoxin A, estrone sulphate, cimetidine (Kusuhara et al., 1999)	–	Ochratoxin A (Youngblood and Sweet, 2004))	Estrone sulphate, dehydroepiandrosterone sulphate, ochratoxin A (Cha et al., 2000)
Stoichiometry	Unknown	Unknown	Unknown	Unknown	Unknown	Unknown

Urate transporter.

Systematic name	SLC22A12
Preferred abbreviation	URAT1
Nomenclature	Urate anion exchanger 1
Ensembl ID	ENSG00000197891
Other names	Renal-specific transporter, RST, organic anion transporter 4-like protein
Endogenous substrates	Urate, orotate (Enomoto et al., 2002)
Stoichiometry	Unknown

Orphan or poorly characterized family members.

Systematic name	Preferred abbreviation	Nomenclature	Ensembl ID	Other names
SLC22A13	ORCTL3	Organic cation transporter-like 3	ENSG00000172940
SLC22A14	ORCTL4	Organic cation transporter-like 4	ENSG00000144671
SLC22A15	FLIPT1	Fly-like putative transporter 1	ENSG00000163393
SLC22A17	BOIT	Brain-type organic cation transporter	ENSG00000092096	BOCT
SLC22A18	ORCTL2	Organic cation transporter-like 2	ENSG00000110628	Imprinted multi-membrane spanning polyspecific transporter-related protein 1, efflux transporter-like protein, tumor-suppressing subchromosomal transferable fragment candidate gene 5 protein, tumor-suppressing STF cDNA 5 protein, Beckwith-Wiedemann syndrome chromosomal region 1 candidate gene A protein
SLC22A20			ENSG00000197847	S22AK_HUMAN Isoform 2 of A6NK97
SLC22A23			ENSG00000137266
SLC22A24			ENSG00000197658
SLC22A25			ENSG00000196600	Organic anion transporter UST6

Abbreviations: MPP, 1-methyl-4-phenylpyridin-1-ium; PAH, p-aminohippurate; TEA, tetraethylammonium

Further Reading

Anderson CM, Thwaites DT (2010). Hijacking solute carriers for proton-coupled drug transport. Physiology (Bethesda)25: 364–377.

Duan P, You G (2010). Short-term regulation of organic anion transporters. Pharmacol Ther125: 55–61.

Koepsell H, Endou H (2004). The SLC22 drug transporter family. Pflugers Arch447: 666–676.

Koepsell H, Lips K, Volk C (2007). Polyspecific organic cation transporters: structure, function, physiological roles, and biopharmaceutical implications. Pharm Res24: 1227–1251.

Miyazaki H, Sekine T, Endou H (2004). The multispecific organic anion transporter family: properties and pharmacological significance. Trends Pharmacol Sci25: 654–662.

Nigam SK, Bush KT, Bhatnagar V (2007). Drug and toxicant handling by the OAT organic anion transporters in the kidney and other tissues. Nat Clin Pract Nephrol3: 443–448.

Saito H (2010). Pathophysiological regulation of renal SLC22A organic ion transporters in acute kidney injury: pharmacological and toxicological implications. Pharmacol Ther125: 79–91.

Sekine T, Miyazaki H, Endou H (2006). Molecular physiology of renal organic anion transporters. Am J Physiol Renal Physiol290: F251–F261.

Zhou F, You G (2007). Molecular insights into the structure-function relationship of organic anion transporters OATs. Pharm Res24: 28–36.

SLC23 family of ascorbic acid transporters

Overview: predicted to be 12 TM segment proteins, members of this family transport the reduced form of ascorbic acid (while the oxidized form may be handled by members of the SLC2 family (GLUT1/SLC2A1, GLUT3/SLC2A3 and GLUT4/SLC2A4, see Page S226).

Systematic name	SLC23A1	SLC23A2	SLC23A3	SLC23A4
Preferred abbreviation	SVCT1	SVCT2	SVCT3	SNBT1
Nomenclature	Sodium-dependent vitamin C transporter 1	Sodium-dependent vitamin C transporter 2	Sodium-dependent vitamin C transporter 3	Sodium-dependent nucleobase transporter
Other names	Yolk sac permease-like molecule 3	Na+/L-ascorbic acid transporter 2, yolk sac permease-like molecule 2, nucleobase transporter-like 1 protein	Yolk sac permease-like molecule 1	–
Ensembl ID	ENSG00000170482	ENSG00000089057	ENSG00000213901	ENSRNOG00000026919
Substrates	l-Ascorbic acid > d-ascorbic acid > dehydroascorbic acid (Tsukaguchi et al., 1999)	l-Ascorbic acid > d-ascorbic acid > dehydroascorbic acid (Tsukaguchi et al., 1999)	–	Uracil > thymine > guanine, hypoxanthine > xanthine, uridine (Yamamoto et al., 2010)
Synthetic substrates	–	–	–	5-Fluorouracil (Yamamoto et al., 2010)
Inhibitors	Phloretin (Tsukaguchi et al., 1999)	–	–
Probes	[14C]-Ascorbic acid	[14C]-Ascorbic acid	–
Stoichiometry	2 Na+: 1 ascorbic acid (in) (Tsukaguchi et al., 1999)	2 Na+: 1 ascorbic acid (in) (Tsukaguchi et al., 1999)	–	1 Na+ : 1 uracil (in) (Yamamoto et al., 2010)

SLC23A3 does not transport ascorbic acid and remains an orphan transporter. SLC23A4/SNBT1 is found in rodents and non-human primates, but the sequence is truncated in the human genome.

Further Reading

Rivas CI, Zuniga FA, Salas-Burgos A, Mardones L, Ormazabal V, Vera JC (2008). Vitamin C transporters. J Physiol Biochem64: 357–375.

Savini I, Rossi A, Pierro C, Avigliano L, Catani MV (2008). SVCT1 and SVCT2: key proteins for vitamin C uptake. Amino Acids34: 347–355.

Takanaga H, Mackenzie B, Hediger MA (2004). Sodium-dependent ascorbic acid transporter family SLC23. Pflugers Arch447: 677–682.

SLC24 family of sodium/potassium/calcium exchangers

Overview: The sodium/potassium/calcium exchange family of transporters utilize the extracellular sodium gradient to drive calcium and potassium co-transport out of the cell. As is the case for NCX transporters (SLC8A family, see page S239), 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.

Systematic name	SLC24A1	SLC24A2	SLC24A3
Preferred abbreviation	NKCX1	NKCX2	NKCX3
Nomenclature	Sodium/potassium/calcium exchanger 1	Sodium/potassium/calcium exchanger 2	Sodium/potassium/calcium exchanger 3
Ensembl ID	ENSG00000074621	ENSG00000155886	ENSG00000185052
Other names	Retinal rod Na-Ca+K exchanger	Retinal cone Na-Ca+K exchanger	–
Stoichiometry	4 Na+:(1Ca2++ 1K+)	–	–

Systematic name	SLC24A4	SLC24A5	SLC24A6
Preferred abbreviation	NKCX4	NKCX5	NKCX6
Nomenclature	Sodium/potassium/calcium exchanger 4	Sodium/potassium/calcium exchanger 5	Sodium/potassium/calcium exchanger 6
Ensembl ID	ENSG00000140090	ENSG00000188467	ENSG00000089060

NKCX6 exhibits sufficient structural diversity for it's function as a NKCX to be questioned (see Altimimi and Schnetkamp, 2007).

To date, there are no agents selective for this family of transporters.

Further Reading

Altimimi HF, Schnetkamp PP (2007). Na⁺/Ca²⁺-K⁺ exchangers (NCKX): functional properties and physiological roles. Channels (Austin)1: 62–69.

Schnetkamp PP (2004). The SLC24 Na⁺/Ca²⁺-K⁺ exchanger family: vision and beyond. Pflugers Arch447: 683–688.

SLC25 family of mitochondrial transporters

Overview: mitochondrial transporters are nuclear-encoded proteins, which convey solutes across the inner mitochondrial membrane. Topological modelling suggests homodimeric transporters, each with six TM segments and termini in the cytosol.

Mitochondrial di- and tri-carboxylic acid transporters are grouped on the basis of commonality of substrates and include the citrate transporter which facititates citrate export from the mitochondria to allow the generation of oxaloacetate and acetylCoA through the action of ATP:citrate lyase.

Systematic name	SLC25A1	SLC25A10	SLC25A11
Common abbreviation	CIC	DIC	OGC
Nomenclature	Mitochondrial citrate transporter	Mitochondrial dicarboxylate transporter	Mitochondrial oxoglutarate carrier
Ensembl ID	ENSG00000100075	ENSG00000183048	ENSG00000108528
Other names	Citrate transport protein, CTP, tricarboxylate carrier protein, citrate isocitrate carrier
Substrates	Citrate, malate, PEP	Malate, phosphate, succinate, sulphate, thiosulphate	Oxoglutarate, malate
Inhibitors	1,2,3-Benzenetricarboxylate		–
Stoichiometry	Malate2− (in) : H-citrate2− (out)	PO34− (in) : malate2− (out)	Malate2− (in) : oxoglutarate2− (out)

Systematic name	SLC25A12	SLC25A13	SLC25A18	SLC25A21	SLC25A22
Common abbreviation	AGC1	AGC2	GC2	OXC	GC1
Nomenclature	Aralar	Citrin	Mitochondrial glutamate carrier 2	Mitochondrial oxodicarboxylate carrier	Mitochondrial glutamate carrier 1
Ensembl ID	ENSG00000115840	ENSG00000004864	ENSG00000182902	ENSG00000183032	ENSG00000177542
Substrates	Aspartate, glutamate, cysteinesulphinate	Aspartate, glutamate, cysteinesulphinate	Glutamate	Oxoadipate, oxoglutarate	Glutamate
Stoichiometry	Aspartate : glutamate H+ (bidirectional)	Aspartate : glutamate H+ (bidirectional)	Glutamate : H+ (bidirectional)	Oxoadipate (in) : oxoglutarate (out)	Glutamate : H+ (bidirectional)

Mitochondrial ornithine transporters play a role in the urea cycle by exchanging cytosolic ornithine for mitochondrial citrulline in equimolar amounts.

Systematic name	SLC25A2	SLC25A15
Common abbreviation	ORC2	ORC1
Nomenclature	Mitochondrial ornithine transporter 2	Mitochondrial ornithine transporter 1
Ensembl ID	ENSG00000120329	ENSG00000102743
Substrates	Ornithine, citrulline, lysine, arginine, histidine (Fiermonte et al., 2003)	L-Ornithine, L-citrulline, L-lysine, L-arginine (Fiermonte et al., 2003)
Stoichiometry	1 Ornithine (in) :1 citrulline : 1 H+ (out)	1 Ornithine (in) :1 citrulline : 1 H+ (out)

Both transporters are inhibited by the polyamine spermine (Fiermonte et al., 2003). Loss-of-function mutations in these genes are associated with hyperornithinemia-hyperammonemia-homocitrullinuria.

Mitochondrial phosphate transporters allow the import of inorganic phosphate for ATP production

Systematic name	SLC25A3
Common abbreviation	PHC
Nomenclature	Mitochondrial phosphate carrier
Ensembl ID	ENSG00000075415
Other names	Phosphate transport protein, PTP, PiC
Stoichiometry	PO34− (in) : OH- (out) or PO34− : H+ (in)

Mitochondrial adenine nucleotide translocator family, under conditions of aerobic metabolism, allow coupling between mitochondrial oxidative phosphorylation and cytosolic energy consumption by exchanging cytosolic ADP for mitochondrial ATP.

Systematic name	SLC25A4	SLC25A5	SLC25A6	SLC25A31
Common abbreviation	ANT1	ANT2	ANT3	ANT4
Nomenclature	Mitochondrial adenine nucleotide translocator 1	Mitochondrial adenine nucleotide translocator 2	Mitochondrial adenine nucleotide translocator 3	Mitochondrial adenine nucleotide translocator 4
Ensembl ID	ENSG00000151729	ENSG00000005022	ENSG00000169100	ENSG00000151475
Other names	Adenine nucleotide translocator 1, ADP,ATP carrier protein 1, ADP,ATP carrier protein, heart/skeletal muscle isoform T1	Adenine nucleotide translocator 2, ADP,ATP carrier protein 2, ADP,ATP carrier protein, fibroblast isoform	Adenine nucleotide translocator 2, ADP,ATP carrier protein 3, ADP,ATP carrier protein, isoform T2	Sperm flagellar energy carrier protein
Inhibitors	CATR, BKA	–	–	–
Stoichiometry	ADP3− (in) : ATP4− (out)	ADP3− (in) : ATP4− (out)	ADP3− (in) : ATP4− (out)	ADP3− (in) : ATP4− (out)

Mitochondrial uncoupling proteins allow dissipation of the mitochondrial proton gradient associated with thermogenesis and regulation of radical formation.

Systematic name	SLC25A7	SLC25A8	SLC25A9	SLC25A27	SLC25A14
Common abbreviation	UCP1	UCP2	UCP3	UCP4	UCP5
Nomenclature	Uncoupling protein 1	Uncoupling protein 2	Uncoupling protein 3
Ensembl ID	ENSG00000109424	ENSG00000175567	ENSG00000175564	ENSG00000153291	ENSG00000102078
Other names	Thermogenin	–	–	–	Brain mitochondrial carrier
Stoichiometry	H+ (in)	H+ (in)	H+ (in)	H+ (in)	H+ (in)

Mitochondrial nucleotide transporters convey nucleotides and their derivatives

Systematic name	SLC25A16	SLC25A17	SLC25A19	SLC25A26	SLC25A42
Common abbreviation	GDC	PMP34	DNC1	SAMC
Nomenclature	Graves disease carrier	Peroxisomal membrane protein	Deoxynucleotide carrier 1	S-Adenosylmethionine carrier
Ensembl ID	ENSG00000122912	ENSG00000100372	ENSG00000125454	ENSG00000144741	ENSG00000181035
Other names	Graves disease autoantigen	–	Mitochondrial thiamine pyrophosphate carrier	–	–
Substrates	CoA and congeners	ATP, ADP, AMP	dNDPs, dNTPs, NDPs, ddNTPs	S-Adenosylmethionine	ADP, Co A (Fiermonte et al., 2009)
Stoichiometry	CoA (in)	ATP (in)	dNDP (in) : ATP (out)

Miscellaneous: many of the transporters identified below have yet to be assigned functions and are currently regarded as orphans.

Systematic name	Common abbreviation	Nomenclature	Ensembl ID	Comments
SLC25A20	CAC	Carnitine/acylcarnitine carrier	ENSG00000178537	Exchanges cytosolic acylcarnitine for mitochondrial carnitine
SLC25A24	APC1	Mitochondrial phosphate carrier 1	ENSG00000085491
SLC25A23	APC2	mitochondrial phosphate carrier 2	ENSG00000125648
SLC25A25	APC3	mitochondrial phosphate carrier 3	ENSG00000148339
SLC25A28		Mitoferrin2	ENSG00000155287
SLC25A29	ORNT3		ENSG00000197119
SLC25A30			ENSG00000174032
SLC25A32	MFTC		ENSG00000164933
SLC25A33			ENSG00000171612
SLC25A34			ENSG00000162461
SLC25A35			ENSG00000125434
SLC25A36			ENSG00000114120
SLC25A37		Mitoferrin1	ENSG00000147454
SLC25A38			ENSG00000144659
SLC25A39			ENSG00000013306
SLC25A40			ENSG00000181240
SLC25A41			ENSG00000181240
SLC25A43			ENSG00000077713
SLC25A44			ENSG00000160785
SLC25A45			ENSG00000162241
SLC25A46			ENSG00000164209

Further relevant information on tabular data. For example, whether agent selectivity is less than 100-fold, whether evidence exists for further subtypes lacking molecular correlates or overlap with other transporter families; relationship with a common genetic disorder.

Abbreviations: BKA, bongkrekic acid; CATR, carboxyatractyloside; PEP, phosphonenolpyruvate

Further Reading

Cioffi F, Senese R, de Lange P, Goglia F, Lanni A, Lombardi A (2009). Uncoupling proteins: a complex journey to function discovery. Biofactors35: 417–428.

Gnoni GV, Priore P, Geelen MJ, Siculella L (2009). The mitochondrial citrate carrier: metabolic role and regulation of its activity and expression. IUBMB Life61: 987–994.

Halestrap AP (2009). What is the mitochondrial permeability transition pore? J Mol Cell Cardiol46: 821–831.

Jezek P, Jaburek M, Garlid KD (2010). Channel character of uncoupling protein-mediated transport. FEBS Lett584: 2135–2141.

Leung AW, Halestrap AP (2008). Recent progress in elucidating the molecular mechanism of the mitochondrial permeability transition pore. Biochim Biophys Acta1777: 946–952.

Palmieri F (2004). The mitochondrial transporter family (SLC25): physiological and pathological implications. Pflugers Arch447: 689–709.

SLC26 family of anion exchangers

Overview: along with the SLC4 family, the SLC26 family acts to allow movement of monovalent and divalent anions across cell membranes. The predicted topology is of 8–14 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.

Selective sulphate transporters

Systematic name	SLC26A1	SLC26A2
Common nomenclature	Sat-1	DTDST
Ensembl ID	ENSG00000145217	ENSG00000155850
Other names	–	–
Substrates	SO42−, oxalate2−	SO42−
Stoichiometry	SO42− (in) : anion (out)	1 SO42− (in) : 2 Cl- (out)

Chloride/bicarbonate exchangers

Systematic name	SLC26A3	SLC26A4	SLC26A6
Common nomenclature	DRA	Pendrin	PAT-1
Ensembl ID	ENSG00000091138	ENSG00000091137	ENSG00000225697
Other names	CLD	–	CFEX
Substrates	Cl-	Cl-, I-, OH-, HCO3-, HCOO-	SO42−, oxalate2−, Cl-, I-, OH-, HCO3-, HCOO-
Stoichiometry	2 Cl- (in) : 1 HCO3- (out) or	Unknown	1 SO42− (in) : 2 HCO3- (out) or
2 Cl- (in) : 1 OH- (out)	1 Cl- (in) : 2 HCO3- (out)

Anion channels

Systematic name	SLC26A7	SLC26A9
Ensembl ID	ENSG00000147606	ENSG00000174502
Ion selectivity	NO3- >> Cl- = Br- = I- > SO42− = Glu-	I- > Br- > NO3- > Cl- > Glu-
Functional characteristics	Voltage- and time-independent current, linear I-V relationship (Kim et al., 2005)	Voltage- and time-independent current, linear I-V relationship (Dorwart et al., 2007)

SLC26A9 has been suggested to operate in two additional modes as a Cl^--HCO₃^- exchanger and as a Na⁺-anion cotransporter (Chang et al., 2009).

Other

Systematic name	SLC26A5	SLC26A8	SLC26A10	SLC26A11
Common nomenclature	Prestin	Tat1	–	–
Ensembl ID	ENSG00000170615	ENSG00000112053	ENSG00000135502	ENSG00000181045
Substrates	Cl-, HCO3-	SO42−, oxalate2−, Cl-		HSO4-
Stoichiometry	Unknown	Unknown	Unknown	Unknown

SLC26A5 has been suggested to function as a molecular motor, rather than a transporter, while SLC26A10 is a possible pseudogene.

Further Reading

Dorwart MR, Shcheynikov N, Yang D, Muallem S (2008). The solute carrier 26 family of proteins in epithelial ion transport. Physiology (Bethesda)23: 104–114.

Kato A, Romero MF (2011). Regulation of electroneutral NaCl absorption by the small intestine. Annu Rev Physiol73: 261–281.

Mount DB, Romero MF (2004). The SLC26 gene family of multifunctional anion exchangers. Pflugers Arch447: 710–721.

Ohana E, Yang D, Shcheynikov N, Muallem S (2009). Diverse transport modes by the solute carrier 26 family of anion transporters. J Physiol587: 2179–2185.

SLC27 family of fatty acid transporters

Overview: Fatty acid transporters are a family of at least one, and possibly six (Schaffer and Lodish, 1994), -TM segment proteins, predicted on the basis of structural similarities to form dimers. These transporters are unusual in that they appear to express intrinsic very long-chain acyl-CoA synthetase (EC 6.2.1.-, EC 6.2.1.7) enzyme activity as well as an intracellular AMP-binding domain. Within the cell, these transporters may associate with plasma and peroxisomal membranes.

Nomenclature	Fatty acid transport protein 1	Fatty acid transport protein 2	Fatty acid transport protein 3
Systematic name	SLC27A1	SLC27A2	SLC27A3
Preferred abbreviation	FATP1	FATP2	FATP3
Ensembl ID	ENSG00000130304	ENSG00000140284	ENSG00000143554
Other names	Long-chain fatty acid transport protein 1	Very-long-chain acyl-CoA synthetase, very-long- chain-fatty-acid-CoA ligase, THCA-CoA ligase, fatty-acid- coenzyme A ligase, very long-chain 1	Long-chain fatty acid transport protein 3, very long-chain acyl-CoA synthetase homolog 3, VLCS-3
Endogenous substrates	C20:4 > C16 > C18:1 > C4 (Schaffer and Lodish, 1994); C16:0 > C18:1 > C18:3 > C8 (Gimeno et al., 2003)	–	–

Nomenclature	Fatty acid transport protein 4	Fatty acid transport protein 5	Fatty acid transport protein 6
Systematic name	SLC27A4	SLC27A5	SLC27A6
Preferred abbreviation	FATP4	FATP5	FATP6
Ensembl ID	ENSG00000167114	ENSG00000083807	ENSG00000113396
Other names	ACSVL4	Bile acyl-CoA synthetase, BACS, bile acid CoA ligase, BAL, cholate-CoA ligase, very long-chain acyl-CoA synthetase homolog 2, VLCSH2	Long-chain fatty acid transport protein 6, very long-chain acyl-CoA synthetase homolog 1, VLCSH1
Endogenous substrates	C16:0 > C18:1 > C4, C18:3 > C20:4 (Stahl et al., 1999); C16:0, C18:1 > C18:3 > C8 (Gimeno et al., 2003)		C16:0 > C18:1 > C18:3 > C8 (Gimeno et al., 2003)

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 CoA to form fatty acyl CoA esters. Small molecule inhibitors of FATP2 (Sandoval et al., 2010) and FATP4 (Blackburn et al., 2006) have been described; analysis of the mechanism of action of some of these inhibitors suggests that transport may be selectively inhibited without altering enzymatic activity of the FATP.

C1-BODIPY-C12 accumulation has been used as a non-selective index of fatty acid transporter activity.

Abbreviations: C12.; C16:0, palmitic acid; C18:0, stearic acid; C18:1, oleic acid; C18:2, linoleic acid; C18:3,n-6, γ-linolenic acid; C2, acetic acid; C20:4, arachidonic acid; C20:5,n-3, 5z,8z,11z,14z,17z-eicosapentaenoic acid, EPA; C22:6,n-3, 4z,7z,10z,13z,16z,19z-docosahexaenoic acid, DHA; C3, propionic acid; C4, butyric acid; C5, valeric acid; C8, octanoic acid

Further Reading

Gimeno RE (2007). Fatty acid transport proteins. Curr Opin Lipidol18: 271–276.

Stahl A (2004). A current review of fatty acid transport proteins (SLC27). Pflugers Arch447: 722–727.

Watkins PA (2008). Very-long-chain acyl-CoA synthetases. J Biol Chem283: 1773–1777.

SLC28 and SLC29 families of nucleoside transporters

Overview: Nucleoside transporters are divided into two families, the sodium-dependent, solute carrier family 28 (SLC28) and the equilibrative, solute carrier family 29 (SLC29), where the endogenous substrates are nucleosides.

SLC28 family members have 13 TM segments with cytoplasmic N-termini and extracellular C-termini.

Systematic name	SLC28A1	SLC28A2	SLC28A3
Common abbreviation	CNT1	CNT2	CNT3
Ensembl ID	ENSG00000156222	ENSG00000137860	ENSG00000099118
Other names	N2/cit, concentrative nucleoside transporter 1	N1/cif, SPNT, concentrative nucleoside transporter 2	N3/cib, concentrative nucleoside transporter 3
Endogenous substrates	Uridine, cytidine, thymidine, adenosine	Adenosine, guanosine, inosine, thymidine	Uridine, cytidine, thymidine, adenosine, guanosine, inosine
Synthetic substrates	AZT, zalcitabine, gemcitabine	Formycin B, cladribine, fludarabine, vidarabine, didanosine	AZT, zalcitabine, didanosine, formycin B, 5-fluorouridine, 5-fluoro-2′-deoxyuridine, zebularine, gemcitabine, cladribine, fludarabine
Predicted stoichiometry	1 Na+ : 1 nucleoside (in)	1 Na+ : 1 nucleoside (in)	2 Na+ : 1 nucleoside (in)

A further two Na⁺-dependent (stoichiometry 1 Na⁺ : 1 nucleoside (in)) nucleoside transporters have been defined on the basis of substrate and inhibitor selectivity: CNT4 (N4/cit, which transports uridine, thymidine and guanosine) and CNT5 (N5/csg, which transports guanosine and adenosine, and may be inhibited by NBTI).

SLC29 family members appear to be composed of 11 TM segments with cytoplasmic N-termini and extracellular C-termini. ENT1 and ENT2 are cell-surface transporters, while ENT3 is intracellular, possibly lysosomal (Baldwin et al., 2005). ENT1-3 are described as broad-spectrum nucleoside transporters. Ahas been reported to be intracellular purine nucleoside transporters

Systematic name	SLC29A1	SLC29A2	SLC29A3	SLC29A4
Common abbreviation	ENT1	ENT2	ENT3	PMAT
Nomenclature	Equilibrative nucleoside transporter 1	Equilibrative nucleoside transporter 2	Equilibrative nucleoside transporter 3	Plasma membrane monoamine transporter
Ensembl ID	ENSG00000112759	ENSG00000174669	ENSG00000156604	ENSG00000164638
Other names	es, NBTI-sensitive	ei, NBTI-insensitive	-	Equilibrative nucleoside transporter 4
Endogenous substrates	Adenosine, guanosine, inosine, uridine, thymidine, cytidine, hypoxanthine, adenine, thymine (Yao et al., 2011)	Adenosine, guanosine, inosine, uridine, thymidine, hypoxanthine	Adenosine, inosine, > guanosine, thymidine, uridine, adenine (Baldwin et al., 2005)	5HT, dopamine > tyramine, histamine (Engel and Wang, 2005)
Synthetic substrates	2-Chloroadenosine, dideoxyinosine, formycin B, tubercidin, vidarabine, cytarabine, cladribine, pentostatin, zalcitabine, didanosine, floxidine, gemcitabine	2-Chloroadenosine, formycin B, tubercidin, cytarabine, cladribine, vidarabine, AZT, gemcitabine	Tubercidin, cordycepin, cladribine, fludarabine, 5-fluoro-2'-deoxyuridine, zebularine, dideoxyinosine, AZT, dideoxycytidine (Baldwin et al., 2005)	MPP+ > TEA (Engel and Wang, 2005)
Selective inhibitors	NBTI (9.7), draflazine (9.5), KF24345 (9.4, Hammond and Archer, 2004), NBTGR (9.3), dilazep (9), dipyridamole (8.5)	–	–	Cimetidine, quinidine, quinine, verapamil, rhodamine123 (Engel and Wang, 2005)
Probes	[3H]-NBTI (0.5 nM), [14C]-adenosine	[14C]-Adenosine	[14C]-Adenosine	–
Predicted stoichiometry	Equilibrative	Equilibrative	Equilibrative	Equilibrative

PMAT also transports adenosine at acidic pH (Barnes et al., 2006; Zhou et al., 2007).

The affinities of draflazine, dilazep, KF24345 and dipyridamole at ENT1 transporters are species dependent, exhibiting lower affinity at rat transporters than at human transporters (Sundaram et al., 1998; Hammond and Archer, 2004).

Abbreviations: 5HT, 5-hydroxytryptamine; AZT, 3′-azido-3′-deoxythymidine; MPP⁺, 1-methyl-4-phenylpyridin-1-ium; NBTI, nitrobenzylthioinosine (also known as NBMPR); NBTGR, nitrobenzylthioguanosine; KF24345, 3-(1-[6,7-diethoxy-2-morpholinoquinazolin-4-yl]piperidin-4-yl)-1,6-dimethyl-2,4(1H,3H)-quinazolinedione hydrochloride

Further Reading

Baldwin SA, Beal PR, Yao SY, King AE, Cass CE, Young JD (2004). The equilibrative nucleoside transporter family, SLC29. Pflugers Arch447: 735–743.

Baldwin SA, McConkey GA, Cass CE, Young JD (2007). Nucleoside transport as a potential target for chemotherapy in malaria. Curr Pharm Des13: 569–580.

Daws LC (2009). Unfaithful neurotransmitter transporters: focus on serotonin uptake and implications for antidepressant efficacy. Pharmacol Ther121: 89–99.

Errasti-Murugarren E, Pastor-Anglada M (2010). Drug transporter pharmacogenetics in nucleoside-based therapies. Pharmacogenomics11: 809–841.

Gray JH, Owen RP, Giacomini KM (2004). The concentrative nucleoside transporter family, SLC28. Pflugers Arch447: 728–734.

King AE, Ackley MA, Cass CE, Young JD, Baldwin SA (2006). Nucleoside transporters: from scavengers to novel therapeutic targets. Trends Pharmacol Sci27: 416–425.

Pastor-Anglada M, Cano-Soldado P, Errasti-Murugarren E, Casado FJ (2008). SLC28 genes and concentrative nucleoside transporter (CNT) proteins. Xenobiotica38: 972–994.

SLC30 zinc transporter family

Overview: Along with the SLC39 family (see Page S270), 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 with subunits having six TM domains, with both termini being cytoplasmic. Dityrosine covalent linking has been suggested as a mechanism for dimerisation, particularly for ZNT3 (Salazar et al., 2009). The mechanism for zinc transport is unknown.

Systematic name	Common abbreviation	Nomenclature	Ensembl ID	Other names
SLC30A1	ZNT1	Zinc transporter 1	ENSG00000170385
SLC30A2	ZNT2	Zinc transporter 2	ENSG00000158014
SLC30A3	ZNT3	Zinc transporter 3	ENSG00000115194
SLC30A4	ZNT4	Zinc transporter 4	ENSG00000104154
SLC30A5	ZNT5	Zinc transporter 5	ENSG00000145740
SLC30A6	ZNT6	Zinc transporter 6	ENSG00000152683
SLC30A7	ZNT7	Zinc transporter 7	ENSG00000162695
SLC30A8	ZNT8	Zinc transporter 8	ENSG00000164756
SLC30A9	ZNT9	Zinc transporter 9	ENSG00000014824	Human embryonic lung protein, HUEL
SLC30A10	ZNT10	Zinc transporter 10	ENSG00000196660

SLC30A8 is described as a type 2 diabetes susceptibility gene.

Zinc fluxes may be monitored through the use of radioisotopic Zn-65 or the fluorescent dye FluoZin 3.

Further Reading

Palmiter RD, Huang L (2004). Efflux and compartmentalization of zinc by members of the SLC30 family of solute carriers. Pflugers Arch447: 744–751.

Rungby J (2010). Zinc, zinc transporters and diabetes. Diabetologia53: 1549–1551.

SLC31 family of copper transporters

Overview: SLC31 family members, alongside the Cu-ATPases (see Page S219) 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 (Rees et al., 2004). 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 (Lee et al., 2002).

Systematic name	SLC31A1	SLC31A2
Preferred abbreviation	CTR1	CTR2
Nomenclature	Copper transporter 1	Copper transporter 2
Ensembl ID	ENSG00000136868	ENSG00000136867
Other names	COPT1	COPT2

Copper accumulation through CTR1 is sensitive to silver ions, but not divalent cations (Lee et al., 2002). The CTR1 and CTR2 transporters regulate the cellular levels of the anticancer drug cisplatin (Ishida et al., 2002, Blair et al., 2009).

Further Reading

De Feo CJ, Aller SG, Unger VM (2007). A structural perspective on copper uptake in eukaryotes. Biometals20: 705–716.

Howell SB, Safaei R, Larson CA, Sailor MJ (2010). Copper transporters and the cellular pharmacology of the platinum-containing cancer drugs. Mol Pharmacol77: 887–894.

Maryon EB, Molloy SA, Zimnicka AM, Kaplan JH (2007). Copper entry into human cells: progress and unanswered questions. Biometals20: 355–364.

Nose Y, Rees EM, Thiele DJ (2006). Structure of the Ctr1 copper trans'PORE'ter reveals novel architecture. Trends Biochem Sci31: 604–607.

Petris MJ (2004). The SLC31 (Ctr) copper transporter family. Pflugers Arch447: 752–755.

SLC32 vesicular inhibitory amino acid transporter

Overview: The vesicular inhibitory amino acid transporter, VIAAT (also termed the vesicular GABA transporter VGAT), which is the sole representative of the SLC32 family, transports GABA, or glycine, into synaptic vesicles (Gasnier, 2000, 2004). VIAAT was originally suggested to be composed of 10 TM segments with cytoplasmic N- and C-termini (McIntire et al., 1997; Sagne et al., 1997). 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 (Martens et al., 2008). VIAAT acts as an antiporter for inhibitory amino acids and protons. The accumulation of GABA and glycine within vesicles is driven by both the chemical (ΔpH) and electrical (Δψ) components of the proton electrochemical gradient (Δµ_H+) established by a vacuolar H⁺-ATPase (McIntire et al., 1997). However, Juge et al. (2009) have presented evidence that VIAAT is instead a Cl^-/GABA co-transporter. VIAAT co-exists with VGLUT1 (SLC17A7), or VGLUT2 (SLC17A6), in the synaptic vesicles of selected nerve terminals (Fattorini et al., 2009; Zander et al., 2010). VIAAT knock out mice die between embryonic day 18.5 and birth (Wojcik et al., 2006). In cultures of spinal cord neurones established from earlier embryos, the co-release of of GABA and glycine from synaptic vesicles is drastically reduced, providing direct evidence for the role of VIAAT in the sequestration of both transmitters (Wojcik et al., 2006; Saito et al., 2010).

Common abbreviation	VIAAT
Systematic name	SLC32A1
Nomenclature	Vesicular inhibitory amino acid transporter
Other names	VGAT (vesicular GABA transporter)
Ensembl ID	ENSG00000101438
Endogenous substrates (Km)	GABA (5 mM; McIntire et al., 1997), glycine, β-alanine, γ-hydroxybutyrate
Synthetic substrates	–
Inhibitors (IC50)	Vigabatrin (7.5 mM; McIntire et al., 1997)
Probes	–
Stoichiometry	1 amino acid (in): 1 H+ (out) (Gasnier, 2004) or 1 amino acid: 2Cl- (in) (Juge et al., 2009)

Further Reading

Erickson JD, De Gois S, Varoqui H, Schafer MK, Weihe E (2006). Activity-dependent regulation of vesicular glutamate and GABA transporters: a means to scale quantal size. Neurochem Int48: 643–649.

Gasnier B (2000). The loading of neurotransmitters into synaptic vesicles. Biochimie82: 327–337.

Gasnier B (2004). The SLC32 transporter, a key protein for the synaptic release of inhibitory amino acids. Pflugers Arch447: 756–759.

SLC33 acetylCoA transporter

Overview: acetylation of proteins is a post-translational modification mediated by specific acetyltransferases, using the donor acetylCoA. SLC33A1/AT1 is a putative 11 TM transporter present on the endoplasmic reticulum, expressed in all tissues, but particularly abundant in the pancreas (Kanamori et al., 1997), which imports cytosolic acetylCoA into these intracellular organelles.

Systematic name	SLC33A1
Preferred abbreviation	AT1
Nomenclature	AcetylCoA transporter
Ensembl ID	ENSG00000169359
Other names	ACATN
Endogenous substrates	AcetylCoA
Probes	[14C]-AcetylCoA
Stoichiometry	Unknown

In heterologous expression studies, acetylCoA transport through AT1 was inhibited by CoA, but not acetate, ATP or UDP-galactose (Jonas et al., 2010). A loss-of-function mutation in SLC33A1 has been associated with spastic paraplegia (SPG42, Lin et al., 2008), although this observation could not be replicated in a subsequent study (Schlipf et al., 2010).

Abbreviations: CoA, coenzyme A, [[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-4-hydroxy-3-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl][(3R)-3-hydroxy-2,2-dimethyl-4-oxo-4-[[3-oxo-3-(2-sulfanylethylamino)propyl]amino]butyl]hydrogen phosphate.

Further Reading

Hirabayashi Y, Kanamori A, Nomura KH, Nomura K (2004). The acetyl-CoA transporter family SLC33. Pflugers Arch447: 760–762.

SLC34 family of sodium phosphate co-transporters

Overview: The SLC34 family are sometimes referred to as Type II sodium-phosphate co-transporters, alongside Type I (SLC17 family, see Page S247) and Type III (SLC20 family, see Page S251) transporters. Topological modelling suggests eight TM domains with C- and N- termini in the cytoplasm, and a re-entrant loop at TM5/6. 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 electrogenic (Andrini et al., 2008).

Systematic name	SLC34A1	SLC34A2	SLC34A3
Common abbreviation	NaPi-IIa	NaPi-IIb	NaPi-IIc
Nomenclature	Sodium phosphate 1	Sodium phosphate 2	Sodium phosphate 3
Ensembl ID	ENSG00000131183	ENSG00000157765	ENSG00000198569
Other names	NAPI-3, NPT2, NPTIIa, SLC11, SLC17A2	NAPI-3B	NPTIIc
Stoichiometry	3 Na+ : 1 HPO42− (in) (Forster et al., 1999)	3 Na+ : 1 HPO42− (in) (Andrini et al., 2008)	2 Na+ : 1 HPO42− (in) (Andrini et al., 2008)

These transporters can be inhibited by PFA, in contrast to type III sodium-phosphate cotransporters, the SLC20 family (see Page S251).

Abbreviations: PFA, phosphonoformic acid

Further Reading

Murer H, Forster I, Biber J (2004). The sodium phosphate cotransporter family SLC34. Pflugers Arch447: 763–767.

SLC35 family of nucleotide sugar transporters

Overview: glycoprotein formation in the Golgi and endoplasmic reticulum relies on the accumulation of nucleotide-conjugated sugars via the SLC35 family of transporters. These transporters have a predicted topology of 10 TM domains, with cytoplasmic termini, and function as exchangers, swopping nucleoside monophosphates for the corresponding nucleoside diphosphate conjugated sugar. Five subfamilies of transporters have been identified on the basis of sequence similarity.

Systematic name	SLC35A1	SLC35A2	SLC35A3	SLC35A4	SLC35A5
Nomenclature	CMP-sialic acid transporter	UDP-galactose transporter	UDP-N-acetylglucosamine transporter	–	–
Ensembl ID	ENSG00000164414	ENSG00000102100	ENSG00000117620	ENSG00000176087	ENSG00000138459
Other names	CMPST, hCST	UGALT, UGAT, UGT, UGT1, UGT2, UGTL	–	–	–
Substrates	CMP-sialic acid (Ishida et al., 1998)	UDP-galactose, UDP-N-acetylglucosamine (Ishida et al., 1996; Miura et al., 1996)	UDP-N-acetylglucosamine (Ishida et al., 1999)	–	–

Systematic name	SLC35B1	SLC35B2	SLC35B3	SLC35B4
Nomenclature	–	PAPS transporter 1	PAPS transporter 2	–
Ensembl ID	ENSG00000121073	ENSG00000157593	ENSG00000124786	ENSG00000205060
Other names	HUT-1	PAPST1, SLL, UGTrel4	PAPST2, C6orf196, CGI-19, dJ453H5.1	YEA4
Substrates	–	PAPS (Kamiyama et al., 2003)	PAPS (Kamiyama et al., 2006)	UDP-xylose, UDP-N-acetylglucosamine (Ashikov et al., 2005)

Systematic name	SLC35C1	SLC35C2
Nomenclature	GDP-Fucose transporter	–
Ensembl ID	ENSG00000181830	ENSG00000080189
Other names	FUCT1	–
Substrates	GDP-fucose (Luhn et al., 2001)	–

Systematic name	SLC35D1	SLC35D2	SLC35D3
Nomenclature	UDP-glucuronic acid/UDP-N-acetylgalactosamine dual transporter	–	–
Ensembl ID	ENSG00000116704	ENSG00000130958	ENSG00000182747
Other names	UDP-galactose transporter-related 7	SQV7-like protein, UDP-galactose transporter-related 8	FRCL1
Substrates	UDP-glucuronic acid, UDP-N-acetylgalactosamine (Muraoka et al., 2001)	UDP-N-acetylgalactosamine (Ishida et al., 2005)	–

Orphan transporters

Systematic name	SLC35E1	SLC35E2	SLC35E3	SLC35E4
Ensembl ID	ENSG00000127526	ENSG00000175782	ENSG00000215790	ENSG00000100036

Systematic name	SLC35F1	SLC35F2	SLC35F3	SLC35F4	SLC35F5
Ensembl ID	ENSG00000196376	ENSG00000110660	ENSG00000183780	ENSG00000151812	ENSG00000115084

Abbreviations: PAPS,[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-4-hydroxy-2-[[oxido(sulfonatooxy)phosphoryl]oxymethyl]oxolan-3-yl] phosphate

Further Reading

Ishida N, Kawakita M (2004). Molecular physiology and pathology of the nucleotide sugar transporter family (SLC35). Pflugers Arch447: 768–775.

SLC36 family of proton-coupled amino acid transporters

Overview: the SLC36 family of proton-coupled amino acid transporters (or PAT) is highly expressed in the intestine and kidney, having roles in the disposition of amino acids (see Thwaites and Anderson, 2011). PAT1 is found predominantly in lysosomal membranes where it likely functions as an efflux mechanism for amino acids produced during intralysosomal proteolysis (Sagnéet al., 2001; Agulhon et al., 2003). PAT2 is found mainly in the endoplasmic reticulum and, to a lesser extent, in other cellular compartments including the plasma membrane (Rubio-Aliaga et al., 2004). PAT1 and PAT2 are predicted to have 11 TM domains with intracellular termini.

Systematic name	SLC36A1	SLC36A2	SLC36A3	SLC36A4
Preferred abbreviation	PAT1	PAT2	PAT3	PAT4
Nomenclature	Proton-coupled Amino acid Transporter 1	Proton-coupled Amino acid Transporter 2	Proton-coupled Amino acid Transporter 3	Proton-coupled Amino acid Transporter 4
Ensembl ID	ENSG00000123643	ENSG00000186335	ENSG00000186334	ENSG00000180773
Other names	LYAAT-1, LYsosomal Amino Acid Transporter 1, imino acid carrier, Tramdorin-3	Tramdorin-1	Tramdorin-2	LYAAT-2
Substrates	GABA, l- and d-proline, glycine, l- and d-alanine, β-alanine, taurine, d-serine, d-cysteine, sarcosine, trans-4-hydroxy-proline, betaine, 5-aminolevulinic acid, β-guanidinopropionic acid	Glycine, proline, alanine, sarcosine, trans-4-hydroxy-proline	–	Proline, tryptophan (Pillai and Meredith, 2011)
Synthetic substrates	MeAIB (Chen et al., 2003a), vigabatrin, THPO, gaboxadol (Larsen et al., 2009)	MeAIB (Chen et al., 2003b)	–	–
Inhibitors	l-Tryptophan, tryptamine, 5-hydroxy-l-tryptophan, serotonin, indole-3-propionic acid (Metzner et al., 2005)	5-Hydroxy-l-tryptophan, α-methyl-d,l-tryptophan (Edwards et al., 2011)	–	–
Probes	[3H] or [14C] substrates as listed above	[3H] or [14C] substrates as listed above	–	–
Stoichiometry	1 H+ : 1 amino acid (in)	1 H+ : 1 amino acid (in)	Unknown	Unknown

Both PAT1 and PAT2 can also function as an electroneutral transport system for H⁺ and fatty acids including acetate, propionate and butyrate (Foltz et al., 2005).

Loss-of-function mutations in PAT2 lead to iminoglycinuria and hyperglycinuria in man (see Bröer, 2008b).

Abbreviations: MeAIB, α- or 2-(methylamino)isobutyric acid; THPO, 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridin-3-ol

Further Reading

Anderson CMH, Thwaites DT (2010). Hijacking solute carriers for proton-coupled drug transport. Physiology25: 364–377.

Bermingham JR, Pennington J (2004). Organization and expression of the SLC36 cluster of amino acid transporter genes. Mamm Genome14: 114–125.

Boll M, Daniel H, Gasnier B (2004). The SLC36 family: proton-coupled transporters for the absorption of selected amino acids from extracellular and intracellular proteolysis. Pflugers Arch447: 776–779.

Bröer S (2008a). Amino acid transport across mammalian intestinal and renal epithelia. Physiol Rev88: 249–286.

Bröer S (2008b). Apical transporters for neutral amino acids: physiology and pathophysiology. Physiology23: 95–103.

Thwaites DT, Anderson CMH (2007). H⁺-coupled nutrient, micronutrient and drug transporters in the mammalian small intestine. Exp Physiol92: 603–619.

Thwaites DT, Anderson CMH (2007). Deciphering the mechanisms of intestinal imino (and amino) acid transport: the redemption of SLC36A1. Biochim Biophys Acta1768: 179–197.

Thwaites DT, Anderson CMH (2011). The SLC36 family of proton-coupled amino acid transporters and their potential role in drug transport. Br J Pharmacol in press.

SLC37 family of phosphosugar/phosphate exchangers

Overview: the family of sugar-phosphate exchangers pass particular phosphorylated sugars across intracellular membranes, exchanging for inorganic phosphate. Of the family of sugar phosphate transporters, most information is available on SPX4, the glucose-6-phosphate transporter. This is a 10 TM domain protein with cytoplasmic termini and is associated with the endoplasmic reticulum, with tissue-specific splice variation. The SPX1 glycerol 3-phosphate transporter is predicted to be expressed on mitochondria.

Systematic name	SLC37A1	SLC37A2	SLC37A3	SLC37A4
Preferred abbreviation	SPX1	SPX2	SPX3	SPX4
Nomenclature	Glycerol-3-phosphate transporter			Glucose-6-phosphate transporter
Ensembl ID	ENSG00000160190	ENSG00000134955	ENSG00000157800	ENSG00000137700
Other names	G3PP	cAMP-inducible gene 2, cI2	–	G6PT1
Substrates	Glycerol 3-phosphate	–	–	Glucose 6-phosphate
Stoichiometry	Unknown	Unknown	Unknown	Unknown

Multiple polymorphisms have been described for the SLC37A4 gene, some of which associate with a glycogen storage disease (Almqvist et al., 2004).

Further Reading

Bartoloni L, Antonarakis SE (2004). The human sugar-phosphate/phosphate exchanger family SLC37. Pflugers Arch447: 780–783.

SLC38 family of sodium-dependent neutral amino acid transporters

Overview: the SLC38 family of transporters appears to be responsible for the functionally-defined system A and system N mechanisms of amino acid transport and are mostly expressed in the CNS. Two distinct subfamilies are identifiable within the SLC38 transporters. SNAT1, SNAT2 and SNAT4 appear to resemble system A transporters in accumulating neutral amino acids under the influence of the sodium gradient. SNAT3 and SNAT5 appear to resemble system N transporters in utilizing proton co-transport to accumulate amino acids. The predicted membrane topology is of 11 TM domains with an extracellular N-terminus and intracellular C-terminus.

System A-like transporters

Systematic name	SLC38A1	SLC38A2	SLC38A4
Preferred abbreviation	SNAT1	SNAT2	SNAT4
Ensembl ID	ENSG00000111371	ENSG00000134294	ENSG00000139209
Other names	Amino acid transporter system A, member 1, ATA1, N-system amino acid transporter 2, NAT2, glutamine transporter	Amino acid transporter system A, member 2, ATA2, SA1, SAT2	Amino acid transporter A3; ATA3, neutral amino acid transporter 3, NAT3, N-system amino acid transporter 3
Substrates	Ala > Ser, Gln, Asn, His, Cys, Met > Gly, Thr, Pro, Tyr, Val (Albers et al., 2001)	Ala, Met > Asn, Gln, Ser, Pro, Gly > Thr, Leu, Phe (Hatanaka et al., 2000)	His > Arg, Ala, Asn, Lys > Gly, Gln, Ser, Pro, Leu, Phe (Hatanaka et al., 2001)
Synthetic substrates	MeAIB	MeAIB	MeAIB
Probes	[3H] or [14C]-Alanine	[3H] or [14C]-Alanine	[3H] or [14C]-Alanine, [3H] or [14C]-glycine
Stoichiometry	1 Na+ : 1 amino acid (in) (Albers et al., 2001)	1 Na+ : 1 amino acid (in) (Hatanaka et al., 2000)	1 Na+ : 1 neutral amino acid (in) (Hatanaka et al., 2001)

Transport of cationic amino acids by SNAT4 was sodium-independent (Hatanaka et al., 2001).

System N-like transporters

Systematic name	SLC38A3	SLC38A5
Preferred abbreviation	SNAT3	SNAT5
Ensembl ID	ENSG00000188338	ENSG00000017483
Other names	Transport system N protein 1, SN1, G17, N-system amino acid transporter 1; NAT1	Transport system N protein 2, SN2
Substrates	His, Gln > Asn, Ala > Glu (Fei et al., 2000)	Asn, Ser, His, Gln > Gly, Ala (Nakanishi et al., 2001)
Synthetic substrates	MeAIB	–
Probes	[3H] or [14C]-Glutamine	[3H] or [14C]-Histidine
Stoichiometry	1 Na+ : 1 amino acid (in) : 1 H+ (out) Broer et al., 2002)	1 Na+ : 1 amino acid (in) : 1 H+ (out) (Nakanishi et al., 2001)

Orphan transporters

Systematic name	SLC38A6	SLC38A7	SLC38A8	SLC38A9	SLC38A10	SLC38A11
Preferred abbreviation	SNAT6	SNAT7	–	–	–	–
Ensembl ID	ENSG00000139974	ENSG00000103042	ENSG00000166558	ENSG00000177058	ENSG00000157637	ENSG00000169507

SNAT7/SLC38A7 has recently been described to be a system N-like transporter allowing preferential accumulation of glutamine, histidine and asparagine (Hagglund et al., 2011).

Abbreviations: MeAIB, 3-amino-2,2-dimethylpropanoic acid

Further Reading

Broer S, Palacin M (2011). The role of amino acid transporters in inherited and acquired diseases. Biochem J436: 193–211.

Mackenzie B, Erickson JD (2004). Sodium-coupled neutral amino acid (System N/A) transporters of the SLC38 gene family. Pflugers Arch447: 784–795.

Sundberg BE, Waag E, Jacobsson JA, Stephansson O, Rumaks J, Svirskis S et al. (2008). The evolutionary history and tissue mapping of amino acid transporters belonging to solute carrier families SLC32, SLC36, and SLC38. J Mol Neurosci35: 179–193.

SLC39 family of metal ion transporters

Overview: along with the SLC30 family (see Page S263), 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. The mechanism for zinc transport for many members is unknown but appears to involve co-transport of bicarbonate ions (Girijashanker et al., 2008, Liu et al., 2008).

Systematic name	SLC39A1	SLC39A2	SLC39A3	SLC39A4	SLC39A5
Common abbreviation	ZIP1	ZIP2	ZIP3	ZIP4	ZIP5
Nomenclature	Zinc transporter 1	Zinc transporter 2	Zinc transporter 3	Zinc transporter 4	metal ion transporter 5
Ensembl ID	ENSG00000143570	ENSG00000165794	ENSG00000141873	ENSG00000206288	ENSG00000139540
Other names	Zinc/iron-regulated transporter-like; ZIRTL, ZRT- and IRT-like protein 1	ZRT- and IRT-like protein 2	ZRT- and IRT-like protein 3	ZRT- and IRT-like protein 4	Metal ion transporter 5

Systematic name	SLC39A6	SLC39A7	SLC39A8	SLC39A9	SLC39A10
Common abbreviation	ZIP6	ZIP7	ZIP8	ZIP9	ZIP10
Nomenclature	Zinc transporter 6	Zinc transporter 7	Zinc transporter 8	Zinc transporter 9	Zinc transporter 10
Ensembl ID	ENSG00000141424	ENSG00000224399; ENSG00000226614; ENSG00000229802; ENSG00000227402; ENSG00000112473	ENSG00000138821	ENSG00000029364	ENSG00000196950
Other names	LIV1	HKE4	BIGM103	–	KIAA1265
Other substrates	–	–	Cadmium (Dalton et al., 2005, Liu et al., 2008)	–	–
Stoichiometry	–	–	1 Zn2+ (in) : 2 HCO3- (in) (Liu et al., 2008)	–	–

Systematic name	SLC39A11	SLC39A12	SLC39A13	SLC39A14
Common abbreviation	ZIP11	ZIP12	ZIP13	ZIP14
Nomenclature	Zinc transporter 11	Zinc transporter 12	Zinc transporter 13	Zinc transporter 14
Ensembl ID	ENSG00000133195	ENSG00000148482	ENSG00000165915	ENSG00000104635
Other names	Metal ion transporter 11	–	–	–
Other substrates	–	–	–	Iron (Liuzzi et al., 2006), cadmium, manganese (Girijashanker et al., 2008)

Zinc fluxes may be monitored through the use of radioisotopic Zn-65 or the fluorescent dye FluoZin 3.

The bicarbonate transport inhibitor DIDS has been reported to inhibit cation accumulation through ZIP14 (Girijashanker K et al., 2008).

Abbreviations: DIDS, 5-isothiocyanato-2-[(E)-2-(4-isothiocyanato-2-sulfophenyl)ethenyl]benzenesulfonic acid

Further Reading

Eide DJ (2004). The SLC39 family of metal ion transporters. Pflugers Arch447: 796–800.

Himeno S, Yanagiya T, Fujishiro H (2009). The role of Zinc transporters in cadmium and manganese transport in mammalian cells. Biochimie91: 1218–1222.

Rungby J (2010). Zinc, Zinc transporters and diabetes. Diabetologia53: 1549–1551.

Thevenod F (2010). Catch me if you can! Novel aspects of cadmium transport in mammalian cells. Biometals23: 857–875.

SLC40 iron transporter

Overview: alongside the SLC11 family (see Page S242) of proton-coupled metal transporters, IREG allows the accumulation of iron from the diet on the basolateral side of the enterocyte, as well as regulating macrophage and placental iron levels. The predicted topology is of nine TM domains, with an intracellular N-terminus and extracellular C-terminus, with the functional transporter is suggested to be a dimeric arrangement (Aguirre et al., 2005; De Domenico et al., 2007).

Systematic name	SLC40A1
Preferred abbreviation	IREG1
Nomenclature	Iron-regulated transporter
Ensembl ID	ENSG00000138449
Other names	Ferroportin, metal transporter protein, MTP1, SLC11A3, FPN1, HFE4
Endogenous substrates	Fe2+
Stoichiometry	Unknown

Hepcidin (HAMP, ENSG00000105697), a small protein that increases upon inflammation, binds to ferroportin to regulate it's cellular distribution and degradation. Gene disruption in mice results in embryonic lethality (Donovan et al., 2005), while loss-of-function mutations in man are associated with haemochromatosis (De Domenico et al., 2005).

Further Reading

McKie AT, Barlow DJ (2004). The SLC40 basolateral iron transporter family (IREG1/ferroportin/MTP1). Pflugers Arch447: 801–806.

SLC41 family of divalent cation transporters

Overview: by analogy with bacterial orthologues, this family is probably magnesium transporters. The prokaryote orthologue, MgtE, is responsible for uptake of divalent cations, while the heterologous expression studies of mammalian proteins suggest Mg²⁺ efflux. Topological modelling suggests 10 TM domains with cytoplasmic C- and N- termini.

Systematic name	SLC41A1	SLC41A2	SLC41A3
Ensembl ID	ENSG00000133065	ENSG00000136052	ENSG00000114544
Substrates	Mg2+, Sr2+, Zn2+, Cu2+, Fe2+, Co2+, Ba2+, Cd2+ (Goytain and Quamme, 2005a)	Mg2+, Ba2+, Ni2+, Co2+, Fe2+, Mn2+ (Goytain and Quamme, 2005b)	–
Stoichiometry	Unknown	Unknown	Unknown

Further Reading

Moomaw AS, Maguire ME (2008). The unique nature of Mg²⁺ channels. Physiology (Bethesda)23: 275–285.

Quamme GA (2010). Molecular identification of ancient and modern mammalian magnesium transporters. Am J Physiol -Cell Physiol298: C407–C429.

SLC42 family of non-erythroid Rhesus glycoprotein ammonium transporters

Overview: Rhesus is commonly defined as a ‘factor’ that determines, in part, blood type, and whether neonates suffer from haemolytic disease of the newborn. These glycoprotein antigens derive from two genes, RHCE (ENSG00000188672) and RHD (ENSG00000187010) 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.

Systematic name	SLC42A1	SLC42A2	SLC42A3
Preferred abbreviation	RhAG	RhBG	RhCG
Ensembl ID	ENSG00000112077	ENSG00000132677	ENSG00000140519
Other names	CD241, RH50A	–	C15orf6, PDRC2, RHGK
Substrates	NH3 (Ripoche et al., 2004), NH4+ (Westhoff et al., 2002), CO2 (Endeward et al., 2008)		NH3 (Zidi-Yahiaoui et al., 2009)
Probes	[14C]-Methylamine	–	[14C]-Methylamine
Stoichiometry	Unknown	Unknown	Unknown

RhBG is a possible pseudogene in man.

Further Reading

Huang CH, Ye M (2010). The Rh protein family: gene evolution, membrane biology, and disease association. Cell Mol Life Sci67: 1203–1218.

Nakhoul NL, Hamm LL (2004). Non-erythroid Rh glycoproteins: a putative new family of mammalian ammonium transporters. Pflugers Arch447: 807–812.

Weiner ID, Verlander JW (2011). Role of NH₃ and NH₄⁺ transporters in renal acid-base transport. Am J Physiol -Renal Physiol300: F11–F23.

SLC43 family of large neutral amino acid transporters

Overview: LAT3 (SLC43A1) and LAT4 (SLC43A2) are transporters with system L amino acid transporter activity, along with the structurally and functionally distinct transporters LAT1 and LAT2 that are members of the SLC7 family (see Page S227). LAT3 and LAT4 contain 12 putative TM domains with both N and C termini located intracellularly. They transport neutral amino acids in a manner independent of Na⁺ and Cl^- and with two kinetic components (Babu et al., 2003; Bodoy et al., 2005). LAT3/SLC43A1 is expressed in human tissues at high levels in the pancreas, liver, skeletal muscle and fetal liver (Babu et al., 2003) whereas LAT4/SLC43A2 is primarily expressed in the placenta, kidney and peripheral blood leukocytes (Bodoy et al., 2005). SLC43A3 is expressed in vascular endothelial cells (Wallgard et al., 2008) but remains to be characterised.

Systematic name	SLC43A1	SLC43A2	SLC43A3
Preferred abbreviation	LAT3	LAT4	–
Nomenclature	L-type amino acid transporter 3	L-type amino acid transporter 4	–
Other names	Large neutral amino acids transporter 1, prostate cancer overexpressed gene 1, POV1	–	–
Ensembl ID	ENSG00000149150	ENSG00000167703	ENSG00000134802
Substrates	L-leucine, L-isoleucine, L-valine, L-phenylalanine, L-methionine	L-leucine, L-isoleucine, L-valine, L-phenylalanine, L-methionine	–
Synthetic substrates	L-leucinol, L-valinol, L-phenylalaninol	L-leucinol, L-valinol	–
Stoichiometry	Operates by facilitative diffusion	Operates by facilitative diffusion	–

Covalent modification of LAT3 by N-ethylmaleimide inhibits its function (Babu et al., 2003) and at LAT4 inhibits the low-, but not high-affinity component of transport (Bodoy et al., 2005).

SLC44 family of choline transporters

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 (Traiffort et al., 2005). CTL family members are putative 10TM domain proteins that mediate Na⁺-independent transport of choline with an affinity that is intermediate to that of the high affinity choline tranporter CHT1 (SLC5A7) and the low affinity organic-cation transporters [OCT1 (SLC22A1) and OCT2 (SLC22A2)] (Michel et al., 2006). CLT1 is expressed almost ubiquitously in human tissues (Wille et al., 2001) and mediates choline transport across the plasma and mitochondrial membranes (Michel and Bakovic, 2009). Transport of choline by CTL2, which in rodents is expressed as two isoforms (CTL2P1 and CLTP2; Kommareddi et al., 2010) in lung, colon, inner ear and spleen and to a lesser extent in brain, tongue, liver, and kidney, has only recently been demonstrated (Kommareddi et al., 2010; Nakamura et al., 2010). CTL3-5 remain to be characterized functionally.

Common name	CTL1	CTL2	CTL3	CTL4	CTL5
Systematic name	SLC44A1	SLC44A2	SLC44A3	SLC44A4	SLC44A5
Nomenclature	Choline transporter-like 1	Choline transporter-like 2	Choline transporter-like 3	Choline transporter-like 4	Choline transporter-like 5
Other names	CHTL1, CDW92	–	–	–	–
Ensembl ID	ENSG00000070214	ENSG00000129353	ENSG00000143036	ENSG00000204385	ENSG00000137968
Substrates	Choline	Choline	–	–	–
Synthetic substrates	–	–	–	–	–
Inhibitors (pKi)	HC-3 (4.5–5.3)	–	–	–	–
Stoichiometry	Unknown: uptake enhanced in the absence of extracellular Na+, reduced by membrane depolarization, extracellular acidification and collapse of plasma membrane H+ electrochemical gradient	–	–	–	–

Data tabulated are features observed for CLT1 endogenous to: rat astrocytes (Inazu et al., 2005); rat renal tubule epithelial cells (Yabuki et al., 2009); human colon carcinoma cells (Kouji et al., 2009); human keratinocytes (Uchida et al., 2009) and human neuroblastoma cells (Yamada et al., 2011). Choline uptake by CLT1 is inhibited by numerous organic cations (e.g.Inazu et al., 2005; Yabuki et al., 2009; Yamada et al., 2011). In the guinea-pig, CTL2 is a target for antibody-induced hearing loss (Nair et al., 2004) and in man a polymorphism in CTL2 constitutes the human neutrophil alloantigen-3a (HNA-3a; Greinacher et al., 2010).

Abbreviations: HC-3, hemicholinium 3

Further Reading

Lockman PR, Allen DD (2002). The transport of choline. Drug Dev Ind Pharm28: 749–771.

Michel V, Yuan Z, Ramsubir S, Bakovic M (2006). Choline transport for phospholipid synthesis. Exp Biol Med (Maywood)231: 490–504.

SLC45 orphans

Overview: Members of the SLC45 family remain to be functionally characterised. However, the SLC45A2 gene is thought to encode a transporter protein that mediates melanin synthesis. Mutations in SLC45A2 are a cause of oculocutaneous albinism type 4 (e.g.Newton et al., 2001), and polymorphisms in this gene are associated with variations in skin and hair color (e.g.Graf et al., 2005).

Systematic name	SLC45A1	SLC45A2	SLC45A3	SLC45A4
Other names	DNB5	Melanin associated transporter protein (MATP), AIM1	Prostate cancer associated protein 6 (PCANAP6), prostein (PRST)	–
Ensembl ID	ENSG00000162426	ENSG00000164175	ENSG00000158715	ENSG00000022567

SLC46 family of folate transporters

Overview: Based on the prototypical member of this family, PCFT, this family are proton-driven transporters with 11 TM segments. SLC46A1 has been described to act as an intestinal proton-coupled high-affinity folate transporter (Qiu et al., 2006), with lower affinity for haem. Folate accumulation is independent of Na⁺ or K⁺ ion concentrations, but driven by extracellular protons with an as-yet undefined stoichiometry.

Systematic name	SLC46A1	SLC46A2	SLC46A3
Preferred abbreviation	PCFT	TSCOT	–
Nomenclature	Proton-coupled folate transporter	Thymic stromal co-transporter	–
Ensembl ID	ENSG00000076351	ENSG00000119457	ENSG00000139508
Other names	Heme carrier protein-1, HCP-1	–	–
Substrates	Folate (1.3 µM) > haem (>100 µM, Nakai et al., 2007)	–	–
Synthetic substrates	Methotrexate (Qiu et al., 2006), folinic acid (Nakai et al., 2007)	–	–
Inhibitors	Sulfasalazine (60 µM, Qiu et al., 2006), indomethacin (∼200 µM, Qiu et al., 2006)	–	–
Probes	[3H]-folate, [3H]-methotrexate	–	–

Loss-of-function mutations in PCFT (SLC46A1) are associated with hereditary folate maladsorption.

Further Reading

Anderson CM, Thwaites DT (2010). Hijacking solute carriers for proton-coupled drug transport. Physiology (Bethesda)25: 364–377.

Krishnamurthy P, Xie T, Schuetz JD (2007). The role of transporters in cellular heme and porphyrin homeostasis. Pharmacol Ther114: 345–358.

Latunde-Dada GO, Simpson RJ, McKie AT (2006). Recent advances in mammalian haem transport. Trends Biochem Sci31: 182–188.

Thwaites DT, Anderson CM (2007). H⁺-coupled nutrient, micronutrient and drug transporters in the mammalian small intestine. Exp Physiol92: 603–619.

Wolf G (2007). Identification of proton-coupled high-affinity human intestinal folate transporter mutated in human hereditary familial folate malabsorption. Nutr Rev65: 554–557.

Yuasa H, Inoue K, Hayashi Y (2009). Molecular and functional characteristics of proton-coupled folate transporter. J Pharm Sci98: 1608–1616.

SLC47 family of multidrug and toxin extrusion transporters

Overview: these proton:organic cation exchangers are predicted to have 13 TM segments (Zhang and Wright, 2009) and are suggested to be responsible for excretion of many drugs in the liver and kidneys.

Systematic name	SLC47A1	SLC47A2
Preferred abbreviation	MATE1	MATE2-K
Nomenclature	Multi antimicrobial extrusion protein
Other names	Multidrug and toxin extrusion protein 1
Ensembl ID	ENSG00000142494	ENSG00000180638
Synthetic substrates	Cimetidine (Ohta et al., 2006), cephalexin, cephadrine, quinidine (Tanihara et al., 2007), paraquat (Chen et al., 2007)	Cimetidine, 1-methyl-4-phenylpyridinium, procainamide, metformin, N1-methylnicotinamide (Masuda et al., 2006), guanidine, acyclovir (Tanihara et al., 2007)
Inhibitors	Pyrimethamine (0.15 µM, Ito et al., 2010)
Probes	[14C]-TEA (Otsuka et al., 2005), [14C]-metformin (Tanihara et al., 2007)	[14C]-TEA (Tanihara et al., 2007)

DAPI has been used to allow quantification of MATE1 and MATE2-mediated transport activity (Yasujima et al., 2010).

Abbreviations: DAPI, 4′,6-diamidino-2-phenylindole; MPP, 1-methyl-4-phenylpyridinium

Further Reading

Terada T, Inui K (2008). Physiological and pharmacokinetic roles of H⁺/organic cation antiporters (MATE/SLC47A). Biochem Pharmacol75: 1689–1696.

Yonezawa A, Inui KI (2011). Importance of the Multidrug and Toxin Extrusion MATE/SLC47A Family to Pharmacokinetics, Pharmacodynamics/Toxicodynamics and Pharmacogenomics. Br J Pharmacol in press.

SLC48 haem transporter

Overview: although identified as a heme transporter (Rajagopal et al., 2008), subsequent evidence suggests this 4TM-containing protein associates with the V-type ATPase (see Page S218) in lysosomes for haem degradation (O'Callaghan et al., 2010). As yet, this transporter awaits characterization.

Systematic name	SLC48A1
Preferred abbreviation	HRG1
Nomenclature	Heme transporter
Ensembl ID	ENSG00000211584
Other names	Heme-responsive gene 1, hHRG-1

SLCO family of organic anion transporting polypeptides

Overview: The SLCO superfamily is comprised of the organic anion transporting polypeptides (OATPs). The 11 human OATPs are divided into 6 families and ten subfamilies based on amino acid identity. These proteins are located on the plasma membrane of cells throughout the body. They have 12 TM domains and intracellular termini, with multiple putative glycosylation sites. OATPs mediate the sodium-independent uptake of a wide range of amphiphilic substrates, including many drugs and toxins. Due to the multispecificity of these proteins, this guide lists classes of substrates and inhibitors for each family member. More comprehensive lists of substrates, inhibitors, and their relative affinities may be found in the review articles listed below.

Nomenclature	OATP1A2	OATP1B1	OATP1B3	OATP1C1
HGNC nomenclature	SLCO1A2	SLCO1B1	SLCO1B3	SLCO1C1
Ensembl ID	ENSG00000084453	ENSG00000134538	ENSG00000111700	ENSG00000139155
Other names	OATP, OATP-A, SLC21A3	OATP-C, OATP2, LST-1, SLC21A6	OATP8, LST-2, SLC21A8	OATP-F, OATP1, SLC21A14, OATP14
Endogenous substrates	Bile acids, bilirubin, BSP, steroid conjugates, thyroid hormones	Bile acids, bilirubin, BSP, leukotrienes, steroid conjugates, thyroid hormones	Bile acids, bilirubin, BSP, CCK-8, leukotriene C4, steroid conjugates, thyroid hormones	Thyroid hormones, steroid conjugates, BSP
Exogenous substrates	Antibiotics, anticancer drugs, beta blockers, deltorphin II, fexofenadine, fluoroquinolones, HIV protease inhibitors, microcystin, ouabain, rosuvastatin, talinolol	ACE inhibitors, anticancer drugs, antifungals, β-lactam antibiotics, bile acid derivatives and conjugates, endothelin receptor antagonists, fexofenadine, HIV protease inhibitors, opioids, rifampicin, sartans, statins	Amanitin, anticancer drugs, β-lactam antibiotics, bile acid derivatives and conjugates, digoxin, erythromycin, fexofenadine, opiods, ouabain, phalloidin, rifampicin, saquinavir, sartans, statins	Statins
Inhibitors	Naringin, rifampicin, rifamycin SV	Cyclosporine A, fibrates, flavonoids, gemfibrozil, glitazones, glycyrrhizin, indocyanine green, macrolide antibiotics rifampicin, rifamycin SV, sildenafil	Cyclosporine A, gemfibrozil, glitazones, glycyrrhizin, HIV protease inhibitors, macrolide antibiotics, rifampicin, rifamycin SV, sildenafil	Probenicid, taurocholate, DPDPE
Common probes	[3H]-BSP, [3H]-DPDPE, [3H]-estrone-3-sulfate	[3H]-estradiol-17β-glucuronide, [3H]-estrone-3-sulfate, pravastatin	[3H]-BSP, [3H]-CCK-8, [3H]-estradiol-17β-glucuronide	[125I]-thyroxine, [3H]-BSP, [3H]-estrone-3-sulfate

Nomenclature	OATP2A1	OATP2B1	OATP3A1
HGNC nomenclature	SLCO2A1	SLCO2B1	SLCO3A1
Ensembl ID	ENSG00000174640	ENSG00000137491	ENSG00000176463
Other names	PGT, SLC21A2	OATP-B, SLC21A9	OATP-D, SLC21A11
Endogenous substrates	Prostaglandins, eicosanoids	BSP, DHEAS, estrone-3-sulfate, thyroxine	Prostaglandins, thyroid hormones, BQ123, vasopressin
Exogenous substrates	Synthetic prostaglandin derivatives	Aliskiren, amiodarone, bosentan, fexofenadine, glibenclamide, statins, talinolol, telmisartan	–
Inhibitors	Bromocresol green, BSP, NSAIDs	Citrus juices, gemfibrozil, glitazones, glyburide, rifamycin SV, rifampicin	–
Common probes	[3H]-prostaglandin E2	[3H]-BSP, [3H]-estrone-3-sulfate	[3H]-estrone-3-sulfate, [3H]-prostaglandin E2

Nomenclature	OATP4A1	OATP4C1	OATP5A1	OATP6A1
HGNC nomenclature	SLCO4A1	SLCO4C1	SLCO5A1	SLCO6A1
Ensembl ID	ENSG00000101187	ENSG00000173930	ENSG00000137571	ENSG00000205359
Other names	OATP-E, SLC21A12	SLC21A20, OATPX, OATP-H, OATP-M1	OATPRP4, OATP-J	OATPY, MGC26949, OATP-I, gonad specific transporter
Endogenous substrates	Steroid conjugates, thyroid hormones, prostaglandins, bile acids	Thyroid hormones, steroid conjugates, cAMP	–	–
Exogenous substrates	Benzylpenicillin	Cardiac glycosides, anticancer drugs, dipeptidyl peptidase-4 inhibitors	–	–
Common probes	[3H]-estrone-3-sulfate	[3H]-digoxin	–	–

Abbreviations: BSP, bromosulfophthalein; CCK-8, Cholecystokinin octapeptide; DHEAS, dehydroepiandrosterone-3-sulfate; DPDPE, [d-Pen2,d-Pen5]-Enkephalin; PGT, prostaglandin transporter

Further Reading

Hagenbuch B (2010). Drug uptake systems in liver and kidney: a historic perspective. Clin Pharmacol Ther87: 39–47.

Hagenbuch B, Meier PJ (2004). Organic anion transporting polypeptides of the OATP/ SLC21 family: phylogenetic classification as OATP/ SLCO superfamily, new nomenclature and molecular/functional properties. Pflugers Arch447: 653–665.

Konig J (2011). Uptake transporters of the human OATP family: molecular characteristics, substrates, their role in drug-drug interactions, and functional consequences of polymorphisms. Handb Exp Pharmacol 1–28.

Niemi M, Pasanen MK, Neuvonen PJ (2011). Organic anion transporting polypeptide 1B1: a genetically polymorphic transporter of major importance for hepatic drug uptake. Pharmacol Rev63: 157–181.