The Concise Guide to PHARMACOLOGY 2013/14: Transporters

Authors


Abstract

The Concise Guide to PHARMACOLOGY 2013/14 provides concise overviews of the key properties of over 2000 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.12444/full.

Transporters are one of the seven major pharmacological targets into which the Guide is divided, with the others being G protein-coupled receptors, ligand-gated ion channels, ion channels, catalytic receptors, nuclear hormone receptors and enzymes. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. A new landscape format has easy to use tables comparing related targets.

It is a condensed version of material contemporary to late 2013, which is presented in greater detail and constantly updated on the website www.guidetopharmacology.org, superseding data presented in previous Guides to Receptors and Channels. It is produced in conjunction with NC-IUPHAR and provides the official IUPHAR classification and nomenclature for human drug targets, where appropriate. It consolidates information previously curated and displayed separately in IUPHAR-DB and the Guide to Receptors and Channels, providing a permanent, citable, point-in-time record that will survive database updates.

An Introduction to Transporters

The majority of biological solutes are charged organic or inorganic molecules. Cellular membranes are hydrophobic and, therefore, effective barriers to separate them allowing the formation of gradients, which can be exploited, for example, in the generation of energy. Membrane transporters carry solutes across cell membranes, which would otherwise be impermeable to them. The energy required for active transport processes is obtained from ATP turnover or by exploiting ion gradients.

ATP-driven transporters can be divided into three major classes: P-type ATPases; F-type or V-type ATPases and ATP-binding cassette transporters. The first of these, P-type ATPases, are multimeric proteins, which transport (primarily) inorganic cations. The second, F-type or V-type ATPases, are proton-coupled motors, which can function either as transporters or as motors. Last, are ATP-binding cassette transporters, heavily involved in drug disposition as well as transporting endogenous solutes.

The second largest family of membrane proteins in the human genome, after the G protein-coupled receptors, are the SLC solute carrier family. Within the solute carrier family, there are not only a great variety of solutes transported, from simple inorganic ions to amino acids and sugars to relatively complex organic molecules like haem. The solute carrier family includes 52 families of almost 400 members. Many of these overlap in terms of the solutes that they carry. For example, amino 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. Some SLC family members remain orphan transporters, in as much as a physiological function has yet to be determined. Within the SLC superfamily, there is an abundance in diversity of structure. Two families (SLC3 and SLC7) only generate functional transporters as heteromeric partners, where one partner is a single TM domain protein. Membrane topology predictions for other families suggest 3, 4, 6, 7, 8, 9, 10, 11, 12, 13, or 14 TM domains. The SLC transporters include members which function as antiports, where solute movement in one direction is balanced by a solute moving in the reverse direction. Symports allow concentration gradients of one solute to allow movement of a second solute across a membrane. A third, relatively small group are equilibrative transporters, which allow solutes to travel across membranes down their concentration gradients. A more complex family of transporters, the SLC27 fatty acid transporters also express enzymatic function. Many of the transporters also express electrogenic properties of ion channels.

Acknowledgements

We wish to acknowledge the tremendous help provided by the Consultants to the Guides past and present (see list in the Overview, p. 1452). We are also extremely grateful for the financial contributions from the British Pharmacological Society, the International Union of Basic and Clinical Pharmacology, the Wellcome Trust (099156/Z/12/Z]), which support the website and the University of Edinburgh, who host the guidetopharmacology.org website.

Conflict of interest

The authors state that there is no conflict of interest to disclose.

List of records presented

ATP-binding cassette transporter family

Overview

ATP-binding cassette transporters are ubiquitous membrane proteins characterized by active ATP-dependent movement of a range of substrates, including ions, lipids, peptides, steroids. Individual subunits are typically made up of two groups of 6TM-spanning domains, with two nucleotide-binding domains (NBD). The majority of eukaryotic ABC transporters are ‘full’ transporters incorporating both TM and NBD entities. Some ABCs, notably the ABCD and ABCG families are half-transporters with only a single membrane spanning domain and one NBD, and are only functional as homo- or heterodimers. Eukaryotic ABC transporters convey substrates from the cytoplasm, either out of the cell or into intracellular organelles. Their role in the efflux of exogenous compounds, notably chemotherapeutic agents, has led to considerable interest.

ABCA subfamily

Systematic nomenclatureCommon abbreviationHGNC, UniProtComment
ABCA1 ABC1, CERPABCA1, O95477 Loss-of-function mutations are associated with Tangier disease, in which plasma HDL cholesterol levels are greatly reduced
ABCA2 ABC2ABCA2, Q9BZC7
ABCA3 ABC3, ABCCABCA3, Q99758 Loss-of-function mutations are associated with pulmonary surfactant deficiency
ABCA4 ABCRABCA4, P78363 Retinal-specific transporter of N-retinylPE; loss-of-function mutations are associated with Stargardt disease, a juvenile onset macular degenerative disease
ABCA5 ABCA5, Q8WWZ7
ABCA6 ABCA6, Q8N139
ABCA7 ABCA7, Q8IZY2 Genome wide association studies identify ABCA7 variants as associated with Alzheimer's Disease [6]
ABCA8 ABCA8, O94911
ABCA9 ABCA9, Q8IUA7
ABCA10 ABCA10, Q8WWZ4
ABCA12 ABCA12, Q86UK0 Reported to play a role in skin ceramide formation [23]
ABCA13 ABCA13, Q86UQ4

Comments

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

ABCB subfamily

Systematic nomenclatureCommon abbreviationHGNC, UniProtComment
ABCB1 MDR1, PGP1ABCB1, P08183 Responsible for the cellular export of many therapeutic drugs. The mouse and rat have two Mdr1 genes (gene names; Mdr1a and Mdr1b) while the human has only the one gene, MDR1
ABCB2 TAP1TAP1, Q03518 Endoplasmic reticulum peptide transporter, possibly requires heterodimerization with TAP2
ABCB3 TAP2TAP2, Q03519 Endoplasmic reticulum peptide transporter, possibly requires heterodimerization with TAP1
ABCB4 PGY3ABCB4, P21439 Transports phosphatidylcholine from intracellular to extracellular face of the hepatocyte canalicular membrane [13]
ABCB5 ABCB5, Q2M3G0 Multidrug resistance protein in, and marker of, melanoma cells [17]
ABCB6 MTABC3ABCB6, Q9NP58 Putative mitochondrial porphyrin transporter [11]; other subcellular localizations are possible, such as the plasma membrane, as a specific determinant of the Langereis blood group system [5]
ABCB7 ABC7ABCB7, O75027 Mitochondrial; reportedly essential for haematopoiesis [15]
ABCB8 MABC1ABCB8, Q9NUT2 Mitochondrial; suggested to play a role in chemoresistance of melanoma [4]
ABCB9 TAPLABCB9, Q9NP78 Reported to be lysosomal [7]
ABCB10 MTABC2ABCB10, Q9NRK6 Mitochondrial location; the first human ABC transporter to have a crystal structure reported [18]
ABCB11 ABC16ABCB11, O95342 Loss-of-function mutations are associated with progressive familial intrahepatic cholestasis type 2 [19]

ABCC subfamily

Systematic nomenclatureCommon abbreviationHGNC, UniProtComment
ABCC1 MRP1ABCC1, P33527 Exhibits a broad substrate specificity [1], including LTC4 (Km 97 nM [12]) and estradiol-17β-glucuronide [20]
ABCC2 MRP2, cMOATABCC2, Q92887 Loss-of-function mutations are associated with Dubin-Johnson syndrome, in which plasma levels of conjugated bilirubin are elevated (OMIM: 237500)
ABCC3 MRP3ABCC3, O15438 Transports conjugates of glutathione, sulfate or glucuronide [2]
ABCC4 MRP4ABCC4, O15439 Although reported to facilitate cellular cyclic nucleotide export, this role has been questioned [2]; reported to export prostaglandins in a manner sensitive to NSAIDS [16]
ABCC5 MRP5ABCC5, O15440 Although reported to facilitate cellular cyclic nucleotide export, this role has been questioned [2]
ABCC6 MRP6ABCC6, O95255 Loss-of-function mutations in ABCC6 are associated with pseudoxanthoma elasticum (OMIM: 264800)
ABCC10 MRP7ABCC10, Q5T3U5
ABCC11 MRP8ABCC11, Q96J66 Single nucleotide polymorphisms distinguish wet vs. dry earwax (OMIM: 117800); an association between earwax allele and breast cancer risk is reported in Japanese but not European populations
ABCC12 MRP9ABCC12, Q96J65

Comments

ABCC7 (also known as CFTR), a 12TM ABC transporter-type protein, is a cAMP-regulated epithelial cell membrane Cl- channel involved in normal fluid transport across various epithelia and can be viewed in the Chloride channels section of the Guide ABCC8 (ENSG00000006071, also known as SUR1, sulfonylurea receptor 1) and ABCC9 (ENSG00000069431, also known as SUR2, sulfonylurea receptor 2) are unusual in that they lack transport capacity but regulate the activity of particular K+ channels (Kir6.1–6.2), conferring nucleotide sensitivity to these channels to generate the canonical KATP channels. ABCC13 (ENSG00000155288) is a possible pseudogene.

ABCD subfamily of peroxisomal ABC transporters

Overview

This family of ‘half-transporters' act as homo- or heterodimers to accumulate fatty acid-CoA esters into peroxisomes for oxidative metabolism [9].

Systematic nomenclatureCommon abbreviationHGNC, UniProtComment
ABCD1 ALDPABCD1, P33897 Transports coenzyme A esters of very long chain fatty acids [21, 22]; loss-of-function mutations in ABCD1 are associated with adrenoleukodystrophy (OMIM: 3001002)
ABCD2 ALDRABCD2, Q9UBJ2 Coenzyme A esters of very long chain unsaturated fatty acids [22]
ABCD3 PMP70ABCD3, P28288

Comments

ABCD4 (ENSG00000119688, also known as PMP69, PXMP1-L or P70R) appears to be located on the endoplasmic reticulum [8], with an unclear function. Loss-of-function mutations in the gene encoding ALDP underlie the metabolic storage disorder X-linked adrenoleukodystrophy.

ABCG subfamily

Overview

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

Systematic nomenclatureCommon abbreviationHGNC, UniProtComment
ABCG1 ABC8ABCG1, P45844 Transports sterols and choline phospholipids [10]
ABCG2 ABCPABCG2, Q9UNQ0 Exhibits a broad substrate specificity, including urate and haem, as well as multiple synthetic compounds [10]. The functional transporter is likely to be a homodimer, although higher oligomeric states have also been proposed
ABCG4 ABCG4, Q9H172 Putative functional dependence on ABCG1
ABCG5 ABCG5, Q9H222 Transports phytosterols and cholesterol; forms an obligate heterodimer with ABCG8. Loss-of-function mutations in ABCG5 are associated with sitosterolemia (OMIM: 210250)
ABCG8 ABCG8, Q9H221 Transports phytosterols and cholesterol; forms an obligate heterodimer with ABCG5. Loss-of-function mutations in ABCG8 are associated with sitosterolemia (OMIM: 210250)

Comments

A further group of ABC transporter-like proteins have been identified to lack membrane spanning regions and are not believed to be functional transporters, but appear to have a role in protein translation [3, 14]: ABCE1 (P61221, also known as OABP or 2'-5' oligoadenylate-binding protein); ABCF1 (Q8NE71, also known as ABC50 or TNF-α-stimulated ABC protein); ABCF2 (Q9UG63, also known as iron-inhibited ABC transporter 2) and ABCF3 (Q9NUQ8).

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 Interact 180: 327339. [PMID:19426719]

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 Sci 35: 3642. [PMID:19819701]

Hinz A, Tampé R. (2012) ABC transporters and immunity: mechanism of self-defense. Biochemistry 51: 49814989. [PMID:22668350]

Kemp S, Theodoulou FL, Wanders RJ. (2011) Mammalian peroxisomal ABC transporters: from endogenous substrates to pathology and clinical significance. Br J Pharmacol 164: 17531766. [PMID:21488864]

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 164: 17671779. [PMID:21175590]

Miller DS. (2010) Regulation of P-glycoprotein and other ABC drug transporters at the blood-brain barrier. Trends Pharmacol Sci 31: 246254. [PMID:20417575]

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 J 23: 12871302. [PMID:19174475]

Ravna AW, Sager G. (2009) Molecular modeling studies of ABC transporters involved in multidrug resistance. Mini Rev Med Chem 9: 186193. [PMID:19200023]

Rees DC, Johnson E, Lewinson O. (2009) ABC transporters: the power to change. Nat Rev Mol Cell Biol 10: 218227. [PMID:19234479]

Seeger MA, van Veen HW. (2009) Molecular basis of multidrug transport by ABC transporters. Biochim Biophys Acta 1794: 725737. [PMID:19135557]

F-type and V-type ATPases

Overview

The F-type (ATP synthase) and the V-type (vacuolar or vesicular proton pump) ATPases, although having distinct subcellular locations and roles, exhibit marked similarities in subunit structure and mechanism. They are both composed of a ‘soluble’ complex (termed F1 or V1) and a membrane complex (Fo or Vo). Within each ATPase complex, the two individual sectors appear to function as connected opposing rotary motors, coupling catalysis of ATP synthesis or hydrolysis to proton transport. Both the F-type and V-type ATPases have been assigned enzyme commission number E.C. 3.6.3.14

F-type ATPase

Overview

The F-type ATPase, also known as ATP synthase or ATP phosphohydrolase (H+-transporting), is a mitochondrial membrane-associated multimeric complex consisting of two domains, an F0 channel domain in the membrane and an F1 domain extending into the lumen. Proton transport across the inner mitochondrial membrane is used to drive the synthesis of ATP, although it is also possible for the enzyme to function as an ATPase. The ATP5O subunit (oligomycin sensitivity-conferring protein, OSCP, (P48047)), acts as a connector between F1 and F0 motors.

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

The F0 motor, responsible for ion translocation, is complex in mammals, with probably nine subunits centring on A, B, and C subunits in the membrane, together with D, E, F2, F6, G2 and 8 subunits. Multiple pseudogenes for the F0 motor proteins have been defined in the human genome.

V-type ATPase

Overview

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

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

The Vo motor, responsible for ion translocation, has six subunits (a-e).

Further reading

El Far O, Seagar M. (2011) A role for V-ATPase subunits in synaptic vesicle fusion?. J Neurochem 117: 603612. [PMID:21375531]

Junge W, Sielaff H, Engelbrecht S. (2009) Torque generation and elastic power transmission in the rotary F(O)F(1)-ATPase. Nature 459: 364370. [PMID:19458712]

Mindell JA. (2012) Lysosomal acidification mechanisms. Annu Rev Physiol 74: 6986. [PMID:22335796]

Nakamoto RK, Baylis Scanlon JA, Al-Shawi MK. (2008) The rotary mechanism of the ATP synthase. Arch Biochem Biophys 476: 4350. [PMID:18515057]

Nakanishi-Matsui M, Sekiya M, Nakamoto RK, Futai M. (2010) The mechanism of rotating proton pumping ATPases. Biochim Biophys Acta 1797: 13431352. [PMID:20170625]

Okuno D, Iino R, Noji H. (2011) Rotation and structure of FoF1-ATP synthase. J Biochem 149: 655664. [PMID:21524994]

von Ballmoos C, Cook GM, Dimroth P. (2008) Unique rotary ATP synthase and its biological diversity. Annu Rev Biophys 37: 4364. [PMID:18573072]

von Ballmoos C, Wiedenmann A, Dimroth P. (2009) Essentials for ATP synthesis by F1F0 ATP synthases. Annu Rev Biochem 78: 649672. [PMID:19489730]

P-type ATPases

Overview

Phosphorylation-type ATPases (EC 3.6.3.-) are associated with membranes and the transport of ions or phospholipids. Characteristics of the family are the transient phosphorylation of the transporters at an aspartate residue and the interconversion between E1 and E2 conformations in the activity cycle of the transporters, taken to represent ‘half-channels' facing the cytoplasm and extracellular/luminal side of the membrane, respectively.

Sequence analysis across multiple species allows the definition of five subfamilies, P1-P5. The P1 subfamily includes heavy metal pumps, such as the copper ATPases. The P2 subfamily includes calcium, sodium/potassium and proton/potassium pumps. The P4 and P5 subfamilies include putative phospholipid flippases.

Na+/K+-ATPases (EC 3.6.3.9)

Overview

The cell-surface Na+/K+-ATPase is an integral membrane protein which regulates the membrane potential of the cell by maintaining gradients of Na+ and K+ ions across the plasma membrane, also making a small, direct contribution to membrane potential, particularly in cardiac cells. For every molecule of ATP hydrolysed, the Na+/K+-ATPase extrudes three Na+ ions and imports two K+ ions. The active transporter is a heteromultimer with incompletely defined stoichiometry, possibly as tetramers of heterodimers, each consisting of one of four large, ten TM domain catalytic α subunits and one of three smaller, single TM domain glycoprotein β-subunits (see table). Additional protein partners known as FXYD proteins (e.g. FXYD2, P54710) appear to associate with and regulate the activity of the pump.

Comments

Na+/K+-ATPases are inhibited by ouabain and cardiac glycosides, such as digoxin, as well as potentially endogenous cardiotonic steroids [24].

Ca2+-ATPases (EC 3.6.3.8)

Overview

The sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) is an intracellular membrane-associated pump for sequestering calcium from the cytosol into intracellular organelles, usually associated with the recovery phase following excitation of muscle and nerves.

The plasma membrane Ca2+-ATPase (PMCA) is a cell-surface pump for extruding calcium from the cytosol, usually associated with the recovery phase following excitation of cells. The active pump is a homodimer, each subunit of which is made up of ten TM segments, with cytosolic C- and N-termini and two large intracellular loops.

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

NomenclatureSERCA1 SERCA2 SERCA3
HGNC, UniProtATP2A1, O14983 ATP2A2, P16615 ATP2A3, Q93084

Comments

The fungal toxin ochratoxin A has been described to activate SERCA in kidney microsomes [25]. cyclopiazonic acid [29], thapsigargin [27] and BHQ are widely employed to block SERCA. Thapsigargin has also been described to block the TRPV1 vanilloid receptor [30].

Comments

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

NomenclatureSPCA1 SPCA2
HGNC, UniProtATP2C1, P98194 ATP2C2, O75185

Comments

Loss-of-function mutations in SPCA1 appear to underlie Hailey-Hailey disease [26].

H+/K+-ATPases (EC 3.6.3.10)

Overview

The H+/K+ ATPase is a heterodimeric protein, made up of α and β subunits. The α subunit has 10 TM domains and exhibits catalytic and pore functions, while the β subunit has a single TM domain, which appears to be required for intracellular trafficking and stabilising the α subunit. The ATP4A and ATP4B subunits are expressed together, while the ATP12A subunit is suggested to be expressed with the β1 (ATP1B1) subunit of the Na+/K+-ATPase [28].

NomenclatureATP4A ATP12A ATP4B
HGNC, UniProtATP4A, P20648 ATP12A, P54707 ATP4B, P51164

Comments

The gastric H+/K+-ATPase is inhibited by proton pump inhibitors used for treating excessive gastric acid secretion, including (R)-lansoprazole and a metabolite of esomeprazole.

Cu+-ATPases (EC 3.6.3.4)

Overview

Copper-transporting ATPases convey copper ions across cell-surface and intracellular membranes. They consist of eight TM domains and associate with multiple copper chaperone proteins (e.g. ATOX1, O00244).

NomenclatureATP7A ATP7B
HGNC, UniProtATP7A, Q04656 ATP7B, P35670

Phospholipid-transporting ATPases (EC 3.6.3.1)

Overview

These transporters are thought to translocate the aminophospholipids phosphatidylserine and phosphatidylethanolamine from one side of the phospholipid bilayer to the other to generate asymmetric membranes. They are also proposed to be involved in the generation of vesicles from intracellular and cell-surface membranes.

Comments

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

A further series of structurally-related proteins have been identified in the human genome, with as yet undefined function, including ATP13A1 (Q9HD20), ATP13A2 (Q9NQ11), ATP13A3 (Q9H7F0), ATP13A4 (Q4VNC1) and ATP13A5 (Q4VNC0).

Further reading

Argüello JM, Raimunda D, González-Guerrero M. (2012) Metal transport across biomembranes: emerging models for a distinct chemistry. J Biol Chem 287: 1351013517. [PMID:22389499]

Benarroch EE. (2011) Na+, K+-ATPase: functions in the nervous system and involvement in neurologic disease. Neurology 76: 287293. [PMID:21242497]

Brini M, Carafoli E. (2009) Calcium pumps in health and disease. Physiol Rev 89: 13411378. [PMID:19789383]

Bublitz M, Musgaard M, Poulsen H, Thøgersen L, Olesen C, Schiøtt B, Morth JP, Møller JV, Nissen P. (2013) Ion pathways in the sarcoplasmic reticulum Ca2+-ATPase. J Biol Chem 288: 1075910765. [PMID:23400778]

Cereijido M, Contreras RG, Shoshani L, Larre I. (2012) The Na+-K+-ATPase as self-adhesion molecule and hormone receptor. Am J Physiol, Cell Physiol 302: C473C481. [PMID:22049208]

Galougahi KK, Liu CC, Bundgaard H, Rasmussen HH. (2012) β-Adrenergic regulation of the cardiac Na+-K+ ATPase mediated by oxidative signaling. Trends Cardiovasc Med 22: 8387. [PMID:23040838]

Gupta SP. (2012) Quantitative structure-activity relationship studies on Na+,K(+)-ATPase inhibitors. Chem Rev 112: 31713192. [PMID:22360614]

Kaler SG. (2011) ATP7A-related copper transport diseases-emerging concepts and future trends. Nat Rev Neurol 7: 1529. [PMID:21221114]

López-Marqués RL, Holthuis JC, Pomorski TG. (2011) Pumping lipids with P4-ATPases. Biol Chem 392: 6776. [PMID:21194369]

Mattle D, Sitsel O, Autzen HE, Meloni G, Gourdon P, Nissen P. (2013) On allosteric modulation of P-type Cu(+)-ATPases. J Mol Biol 425: 22992308. [PMID:23500486]

Michelangeli F, East JM. (2011) A diversity of SERCA Ca2+ pump inhibitors. Biochem Soc Trans 39: 789797. [PMID:21599650]

Morth JP, Pedersen BP, Buch-Pedersen MJ, Andersen JP, Vilsen B, Palmgren MG, Nissen P. (2011) A structural overview of the plasma membrane Na+,K+-ATPase and H+-ATPase ion pumps. Nat Rev Mol Cell Biol 12: 6070. [PMID:21179061]

Palmgren MG, Nissen P. (2011) P-type ATPases. Annu Rev Biophys 40: 243266. [PMID:21351879]

Pittman JK. (2011) Vacuolar Ca(2+) uptake. Cell Calcium 50: 139146. [PMID:21310481]

Pizzo P, Lissandron V, Capitanio P, Pozzan T. (2011) Ca(2+) signalling in the Golgi apparatus. Cell Calcium 50: 184192. [PMID:21316101]

Reinhard L, Tidow H, Clausen MJ, Nissen P. (2013) Na(+),K (+)-ATPase as a docking station: protein-protein complexes of the Na(+),K (+)-ATPase. Cell Mol Life Sci 70: 205222. [PMID:22695678]

Sebastian TT, Baldridge RD, Xu P, Graham TR. (2012) Phospholipid flippases: building asymmetric membranes and transport vesicles. Biochim Biophys Acta 1821: 10681077. [PMID:22234261]

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 [31, 37, 64, 65, 76].

Glutamate transporter subfamily

Overview

Glutamate transporters present the unusual structural motif of 8TM segments and 2 re-entrant loops [60]. The crystal structure of a glutamate transporter homologue (GltPh) from Pyrococcus horikoshii supports this topology and indicates that the transporter assembles as a trimer, where each monomer is a functional unit capable of substrate permeation [38, 78, 93] reviewed by [63]). This structural data is in agreement with the proposed quaternary structure for EAAT2 [55] and several functional studies that propose the monomer is the functional unit [57, 67, 69, 83]. Recent evidence suggests that EAAT3 and EAAT4 may assemble as heterotrimers [74]. The activity of glutamate transporters located upon both neurones (predominantly EAAT3, 4 and 5) and glia (predominantly EAAT 1 and 2) serves, dependent upon their location, to regulate excitatory neurotransmission, maintain low ambient extracellular concentrations of glutamate (protecting against excitotoxicity) and provide glutamate for metabolism including the glutamate-glutamine cycle. The Na+/K+-ATPase that maintains the ion gradients that drive transport has been demonstrated to co-assemble with EAAT1 and EAAT2 [80]. Recent evidence supports altered glutamate transport and novel roles in brain for splice variants of EAAT1 and EAAT2 [54, 70]. Three patients with dicarboxylic aminoaciduria (DA) were recently found to have loss-of-function mutations in EAAT3 [36]. DA is characterized by excessive excretion of the acidic amino acids glutamate and aspartate and EAAT3 is the predominant glutamate/aspartate transporter in the kidney. Enhanced expression of EAAT2 resulting from administration of β-lactam antibiotics (e.g. ceftriaxone) is neuroprotective and occurs through NF-κB-mediated EAAT2 promoter activation [53, 71, 81] reviewed by [66]). PPARγ activation (e.g. by rosiglitazone) also leads to enhanced expression of EAAT though promoter activation [79]. In addition, several translational activators of EAAT2 have recently been described [42] along with treatments that increase the surface expression of EAAT2 (e.g. [68]; [98]), or prevent its down-regulation (e.g. [56]). A thermodynamically uncoupled Cl- flux, activated by Na+ and glutamate [59, 64, 73] (Na+ and aspartate in the case of GltPh [82]), is sufficiently large, in the instances of EAAT4 and EAAT5, to influence neuronal excitability [88, 92]. 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 [52].

NomenclatureExcitatory amino acid transporter 1 Excitatory amino acid transporter 2 Excitatory amino acid transporter 3 Excitatory amino acid transporter 4 Excitatory amino acid transporter 5
Systematic nomenclatureSLC1A3SLC1A2SLC1A1SLC1A6SLC1A7
Common abbreviationEAAT1EAAT2EAAT3EAAT4EAAT5
HGNC, UniProtSLC1A3, P43003 SLC1A2, P43004 SLC1A1, P43005 SLC1A6, P48664 SLC1A7, O00341
Endogenous substratesL-glutamic acid, L-aspartic acid L-glutamic acid, L-aspartic acid L-glutamic acid, L-aspartic acid, L-cysteine [94]L-glutamic acid, L-aspartic acid L-glutamic acid, L-aspartic acid
SubstratesDL-threo-β-hydroxyaspartate, L-trans-2,4-pyrolidine dicarboxylate, D-aspartic acid DL-threo-β-hydroxyaspartate, L-trans-2,4-pyrolidine dicarboxylate, D-aspartic acid DL-threo-β-hydroxyaspartate, L-trans-2,4-pyrolidine dicarboxylate, D-aspartic acid DL-threo-β-hydroxyaspartate, L-trans-2,4-pyrolidine dicarboxylate, D-aspartic acid DL-threo-β-hydroxyaspartate, L-trans-2,4-pyrolidine dicarboxylate, D-aspartic acid
Inhibitors (pIC50)DL-TBOA (pKB 5.0) [85], UCPH-101 (membrane potential assay) (6.9) [62]DL-TBOA (pKB 6.9) [85], SYM2081 (pKB 5.5) [91], dihydrokainate (pKB 5.0), threo-3-methylglutamate (pKB 4.7) [91], WAY-213613 (6.9)NBI-59159 (7.6), L-β-BA ([3H]D-aspartate uptake assay) (6.1), DL-TBOA (5.1)DL-TBOA (pKi 5.4) [84], threo-3-methylglutamate (pKi 4.3) [47]DL-TBOA (pKi 5.5) [84]
Radioligands (Kd)[3H](2S,4R)-4-methylglutamate, [3H]D-aspartic acid, [3H]L-aspartic acid, [3H]ETB-TBOA (1.55x10−8 M)[3H](2S,4R)-4-methylglutamate, [3H]D-aspartic acid, [3H]L-aspartic acid, [3H]ETB-TBOA (1.62x10−8 M)[3H]D-aspartic acid, [3H]L-aspartic acid, [3H]ETB-TBOA (3.2x10−7 M)[3H]D-aspartic acid, [3H]L-aspartic acid, [3H]ETB-TBOA (2.48x10−8 M)[3H]D-aspartic acid, [3H]L-aspartic acid, [3H]ETB-TBOA (2.95x10−8 M)
StoichiometryProbably 3 Na+: 1 H+ : 1 glutamate (in): 1 K+ (out)3 Na+: 1 H+ : 1 glutamate (in): 1 K+ (out) [72]3 Na+: 1 H+ : 1 glutamate (in): 1 K+ (out) [95]Probably 3 Na+: 1 H+ : 1 glutamate (in): 1 K+(out)Probably 3 Na+: 1 H+ : 1 glutamate (in): 1 K+ (out)

Comments

The KB (or Ki) values reported, unless indicated otherwise, are derived from transporter currents mediated by EAATs expressed in voltage-clamped Xenopus laevis oocytes [47, 84, 85, 91]. KB (or Ki) values derived in uptake assays are generally higher (e.g. [85]). In addition to acting as a poorly transportable inhibitor of EAAT2, (2S,4R)-4-methylglutamate, also known as SYM2081, is a competitive substrate for EAAT1 (KM = 54μM; [61, 91]) and additionally is a potent kainate receptor agonist [97] which renders the compound unsuitable for autoradiographic localisation of EAATs [33]. Similarly, at concentrations that inhibit EAAT2, dihydrokainate binds to kainate receptors [85]. WAY-855 and WAY-213613 are both non-substrate inhibitors with a preference for EAAT2 over EAAT3 and EAAT1 [45, 46]. NBI-59159 is a non-substrate inhibitor with modest selectivity for EAAT3 over EAAT1 (>10-fold) and EAAT2 (5-fold) [43, 44]. Analogously, L-β-threo-benzyl-aspartate (L-β-BA) is a competitive non-substrate inhibitor that preferentially blocks EAAT3 versus EAAT1, or EAAT2 [48]. [3H](2S,4R)-4-methylglutamate demonstrates low affinity binding (KD ≅ 6.0 μM) to EAAT1 and EAAT2 in rat brain homogenates [34] and EAAT1 in murine astrocyte membranes [32], whereas [3H]ETB-TBOA binds with high affinity to all EAATs other than EAAT3 [86]. The novel isoxazole derivative (–)-HIP-A may interact at the same site as TBOA and preferentially inhibit reverse transport of glutamate [41]. 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 [47]. parawixin 1, a compound isolated from the venom from the spider Parawixia bistriata is a selective enhancer of the glutamate uptake through EAAT2 but not through EAAT1 or EAAT3 [50, 51]. 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 [90]).

Alanine/serine/cysteine transporter subfamily

Overview

ASC transporters mediate Na+-dependent exchange of small neutral amino acids such as Ala, Ser, Cys and Thr and their structure is predicted to be similar to that of the glutamate transporters [35, 89]. ASCT1 and ASCT2 also exhibit thermodynamically uncoupled chloride channel activity associated with substrate transport [40, 96]. Whereas EAATs counter-transport K+ (see above) ASCTs do not and their function is independent of the intracellular concentration of K+ [96].

NomenclatureAlanine/serine/cysteine transporter 1 Alanine/serine/cysteine transporter 2
Systematic nomenclatureSLC1A4SLC1A5
Common abbreviationASCT1ASCT2
HGNC, UniProtSLC1A4, P43007 SLC1A5, Q15758
Endogenous substratesL-cysteine > L-alanine = L-serine > L-threonine L-alanine = L-serine = L-cysteine (low Vmax) = L-threonine = L-glutamine = L-asparagine >> L-methionineglycineL-leucine > L-valine > L-glutamic acid (enhanced at low pH)
Inhibitors (pIC50)benzylcysteine [58], benzylserine [58], p-nitrophenyl glutamyl anilide [49]
Stoichiometry1 Na+: 1 amino acid (in): 1 Na+: 1 amino acid (out); (homo-, or hetero-exchange; [95])1 Na+: 1 amino acid (in): 1 Na+: 1 amino acid (out); (homo-, or hetero-exchange; [39])

Comments

The substrate specificity of ASCT1 may extend to L-proline and L-hydroxyproline [77]. At low pH (∼5.5) both ASCT1 and ASCT2 are able to exchange acidic amino acids such as L-cysteate and glutamate [87, 89]. In addition to the inhibitors tabulated above, HgCl2, methylmercury, mersalyl, at low micromolar concentrations, non-competitively inhibit ASCT2 by covalent modificiation of cysteine residues [75].

Further reading

Bröer S, Palacín M. (2011) The role of amino acid transporters in inherited and acquired diseases. Biochem J 436: 193211. [PMID:21568940]

Chao XD, Fei F, Fei Z. (2010) The role of excitatory amino acid transporters in cerebral ischemia. Neurochem Res 35: 12241230. [PMID:20440555]

Jiang J, Amara SG. (2011) New views of glutamate transporter structure and function: advances and challenges. Neuropharmacology 60: 172181. [PMID:20708631]

Kanai Y, Clémençon B, Simonin A, Leuenberger M, Lochner M, Weisstanner M, Hediger MA. (2013) The SLC1 high-affinity glutamate and neutral amino acid transporter family. Mol Aspects Med 34: 108120. [PMID:23506861]

Kim K, Lee SG, Kegelman TP, Su ZZ, Das SK, Dash R, Dasgupta S, Barral PM, Hedvat M, Diaz P et al. (2011) Role of excitatory amino acid transporter-2 (EAAT2) and glutamate in neurodegeneration: opportunities for developing novel therapeutics. J Cell Physiol 226: 24842493. [PMID:21792905]

SLC2 family of hexose and sugar alcohol transporters

Overview

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

Class I transporters

Overview

Class I transporters are able to transport D-glucose, but not D-fructose, in the direction of the concentration gradient and may be inhibited non-selectively by phloretin and cytochalasin B. GLUT1 is the major glucose transporter in brain, placenta and erythrocytes, GLUT2 is found in the pancreas, liver and kidneys, GLUT3 is neuronal and placental, while GLUT4 is the insulin-responsive transporter found in skeletal muscle, heart and adipose tissue. GLUT14 appears to result from gene duplication of GLUT3 and is expressed in the testes [105].

NomenclatureGlucose transporter 1 Glucose transporter 2 Glucose transporter 3 Glucose transporter 4 Glucose transporter 14
Systematic nomenclatureSLC2A1SLC2A2SLC2A3SLC2A4SLC2A14
Common abbreviationGLUT1GLUT2GLUT3GLUT4GLUT14
HGNC, UniProtSLC2A1, P11166 SLC2A2, P11168 SLC2A3, P11169 SLC2A4, P14672 SLC2A14, Q8TDB8
SubstratesD-glucose = D-glucosamine [104], dehydroascorbic acid [99]D-glucosamine > D-glucose [104]D-glucose D-glucosamine ≥ D-glucose [104]
Radioligands (Kd)[3H]2-deoxyglucose [3H]2-deoxyglucose [3H]2-deoxyglucose [3H]2-deoxyglucose

Class II transporters

Overview

Class II transporters transport D-fructose and appear to be insensitive to cytochalasin B. Class II transporters appear to be predominantly intracellularly located.

NomenclatureGlucose transporter 6 Glucose transporter 8 Glucose transporter 10 Glucose transporter 12
Systematic nomenclatureSLC2A6SLC2A8SLC2A10SLC2A12
Common abbreviationGLUT6GLUT8GLUT10GLUT12
HGNC, UniProtSLC2A6, Q9UGQ3 SLC2A8, Q9NY64 SLC2A10, O95528 SLC2A12, Q8TD20
SubstratesD-glucose [101]D-glucose [102], dehydroascorbic acid [102]D-glucose [103]

Proton-coupled inositol transporter

Overview

Proton-coupled inositol transporters are expressed predominantly in the brain and can be inhibited by phloretin and cytochalasin B [104].

NomenclatureProton myo-inositol cotransporter
Systematic nomenclatureSLC2A13
Common abbreviationHMIT
HGNC, UniProtSLC2A13, Q96QE2
Substratesmyo-inositol [104], D-chiro-inositol [104], muco-inositol [104], scyllo-inositol [104]
Stoichiometry1 H+ : 1 inositol (in) [100]

Further reading

Augustin R. (2010) The protein family of glucose transport facilitators: It's not only about glucose after all. IUBMB Life 62: 315333. [PMID:20209635]

Leney SE, Tavaré JM. (2009) The molecular basis of insulin-stimulated glucose uptake: signalling, trafficking and potential drug targets. J Endocrinol 203: 118. [PMID:19389739]

Mueckler M, Thorens B. (2013) The SLC2 (GLUT) family of membrane transporters. Mol Aspects Med 34: 121138. [PMID:23506862]

Uldry M, Thorens B. (2004) The SLC2 family of facilitated hexose and polyol transporters. Pflugers Arch 447: 480489. [PMID:12750891]

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

Overview

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

SLC3 family

Overview

SLC3 family members are single TM proteins with extensive glycosylation of the exterior C-terminus, which heterodimerize with SLC7 family members in the endoplasmic reticulum and assist in the plasma membrane localization of the transporter.

NomenclaturerBAT 4F2hc
Systematic nomenclatureSLC3A1SLC3A2
Common abbreviationrBAT4F2hc
HGNC, UniProtSLC3A1, Q07837 SLC3A2, P08195

SLC7 family

Overview

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

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

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.

Comments

CAT4 appears to be non-functional in heterologous expression [106], while SLC7A14 has yet to be characterized.

Heterodimers between 4F2hc and LAT1 or LAT2 generate sodium-independent system L transporters. LAT1 transports large neutral amino acids including branched-chain and aromatic amino acids as well as miglustat, whereas LAT2 transports most of the neutral amino acids.

Heterodimers between 4F2hc and y+LAT1 or y+LAT2 generate transporters similar to the system y+L , which transport cationic (L-arginine, L-lysine, L-ornithine) amino acids independent of sodium and neutral (L-leucine, L-isoleucine, L-methionine, L-glutamine) amino acids in a partially sodium-dependent manner. These transporters are N-ethylmaleimide-insensitive. Heterodimers between rBAT and b0,+AT appear to mediate sodium-independent system b0,+ transport of most of the neutral amino acids and cationic amino acids (L-arginine, L-lysine and L-ornithine).

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

xCT generates a heterodimer with 4F2hc for a system x-e-c transporter that mediates the sodium-independent exchange of L-cystine and L-glutamic acid.

AGT has been conjugated with SLC3 members as fusion proteins to generate functional transporters, but the identity of a native heterodimer has yet to be ascertained.

Further reading

Closs EI, Boissel JP, Habermeier A, Rotmann A. (2006) Structure and function of cationic amino acid transporters (CATs). J Membr Biol 213: 6777. [PMID:17417706]

Fotiadis D, Kanai Y, Palacín M. (2013) The SLC3 and SLC7 families of amino acid transporters. Mol Aspects Med 34: 139158. [PMID:23506863]

Palacín M, Kanai Y. (2004) The ancillary proteins of HATs: SLC3 family of amino acid transporters. Pflugers Arch 447: 490494. [PMID:14770309]

Palacín M, Nunes V, Font-Llitjós M, Jiménez-Vidal M, Fort J, Gasol E, Pineda M, Feliubadaló L, Chillarón J, Zorzano A. (2005) The genetics of heteromeric amino acid transporters. Physiology (Bethesda) 20: 112124. [PMID:15772300]

Verrey F, Closs EI, Wagner CA, Palacin M, Endou H, Kanai Y. (2004) CATs and HATs: the SLC7 family of amino acid transporters. Pflugers Arch 447: 532542. [PMID:14770310]

SLC4 family of bicarbonate transporters

Overview

Together with the SLC26 family, the SLC4 family of transporters subserve anion exchange, principally of chloride and bicarbonate (HCO3-), but also carbonate and hydrogen sulphate (HSO4-). SLC4 family members regulate bicarbonate fluxes as part of carbon dioxide movement, chyme neutralization and reabsorption in the kidney.

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

Anion exchangers

NomenclatureAnion exchange protein 1 Anion exchange protein 2 Anion exchange protein 3 Anion exchange protein 4
Systematic nomenclatureSLC4A1SLC4A2SLC4A3SLC4A9
Common abbreviationAE1AE2AE3AE4
HGNC, UniProtSLC4A1, P02730 SLC4A2, P04920 SLC4A3, P48751 SLC4A9, Q96Q91
Endogenous substratesCl-, HCO3- Cl-, HCO3- Cl-, HCO3-
Stoichiometry1 Cl- (in) : 1 HCO3- (out)1 Cl- (in) : 1 HCO3- (out)1 Cl- (in) : 1 HCO3- (out)

Sodium-dependent HCO3- transporters

NomenclatureElectrogenic sodium bicarbonate cotransporter 1 Electrogenic sodium bicarbonate cotransporter 4 Electroneutral sodium bicarbonate cotransporter 1 Electroneutral sodium bicarbonate cotransporter 2 NBCBE NaBC1
Systematic nomenclatureSLC4A4SLC4A5SLC4A7SLC4A10SLC4A8SLC4A11
Common abbreviationNBCe1NBCe2NBCn1NBCn2NDCBEBTR1
HGNC, UniProtSLC4A4, Q9Y6R1 SLC4A5, Q9BY07 SLC4A7, Q9Y6M7 SLC4A10, Q6U841 SLC4A8, Q2Y0W8 SLC4A11, Q8NBS3
Endogenous substratesNaHCO3- NaHCO3- NaHCO3- NaHCO3- Cl-, NaHCO3- Cl-, NaHCO3-
Stoichiometry1 Na+ : 2/3 HCO3- (out) or 1 Na+ : CO32*1 Na+ : 2/3 HCO3- (out) or 1 Na+ : CO32*1 Na+ : 1 HCO3- (out) or 1 Na+ : CO32*1 Na+ : 1 HCO3- (out) or 1 Na : CO32*1 Na+ : 2HCO3- (in) : 1 Cl- (out)

Further reading

Alper SL. (2009) Molecular physiology and genetics of Na+-independent SLC4 anion exchangers. J Exp Biol 212 (Pt 11): 16721683. [PMID:19448077]

Boron WF, Chen L, Parker MD. (2009) Modular structure of sodium-coupled bicarbonate transporters. J Exp Biol 212 (Pt 11): 16971706. [PMID:19448079]

Liu Y, Wang DK, Chen LM. (2012) The physiology of bicarbonate transporters in mammalian reproduction. Biol Reprod 86: 99. [PMID:22262691]

Majumdar D, Bevensee MO. (2010) Na-coupled bicarbonate transporters of the solute carrier 4 family in the nervous system: function, localization, and relevance to neurologic function. Neuroscience 171: 951972. [PMID:20884330]

Parker MD, Boron WF. (2013) The divergence, actions, roles, and relatives of sodium-coupled bicarbonate transporters. Physiol Rev 93: 803959. [PMID:23589833]

Romero MF, Chen AP, Parker MD, Boron WF. (2013) The SLC4 family of bicarbonate (HCO3) transporters. Mol Aspects Med 34: 159182. [PMID:23506864]

SLC5 family of sodium-dependent glucose transporters

Overview

The SLC5 family of sodium-dependent glucose transporters includes, in mammals, the Na+/substrate co-transporters for glucose (e.g. choline), D-glucose, monocarboxylates, myo-inositol and I- [121, 122, 142, 143]. 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 [107].

Hexose transporter family

Overview

Detailed characterisation of members of the hexose transporter family is limited to SGLT1, 2 and 3, which are all inhibited in a competitive manner by phlorizin, a natural dihydrocholine glucoside, that exhibits modest selectivity towards SGLT2 (see [142] for an extensive review). SGLT1 is predominantly expressed in the small intestine, mediating the absorption of glucose (e.g. D-glucose), but also occurs in the brain, heart and in the late proximal straight tubule of the kidney. The expression of SGLT2 is almost exclusively restricted to the early proximal convoluted tubule of the kidney, where it is largely responsible for the renal reabsorption of glucose. SGLT3 is not a transporter but instead acts as a glucosensor generating an inwardly directed flux of Na+ that causes membrane depolarization [117].

NomenclatureSGLT1 SGLT2 SGLT3 SGLT4 SGLT5
Systematic nomenclatureSLC5A1SLC5A2SLC5A4SLC5A9SLC5A10
Common abbreviationSGLT1SGLT2SGLT3SGLT4SGLT5
HGNC, UniProtSLC5A1, P13866 SLC5A2, P31639 SLC5A4, Q9NY91 SLC5A9, Q2M3M2 SLC5A10, A0PJK1
SubstratesD-glucose, α-MDG, D-galactose D-glucose, α-MDG D-glucose, N-ethyl-1-deoxynojirimycin, 1-deoxynojirimycin, 1-deoxynojirimycin-1-sulfonic acid, miglustat, miglitol D-glucose, α-MDG, D-mannose D-glucose, D-galactose
Inhibitors (pIC50)remogliflozin (pKi 5.4), sergliflozin (pKi 5.1), canagliflozin (6.4), dapagliflozin (5.9), empagliflozin (5.1)remogliflozin (pKi 7.9), sergliflozin (pKi 6.8), dapagliflozin (9.0), canagliflozin (8.7), empagliflozin (8.5)
Stoichiometry2 Na+ : 1 glucose [129]1 Na+ : 1 glucose [127]

Comments

Recognition and transport of substrate by SGLTs requires that the sugar is a pyranose. De-oxyglucose derivatives have reduced affinity for SGLT1, but the replacement of the sugar equatorial hydroxyl group by fluorine at some positions, excepting C2 and C3, is tolerated (see [142] 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 [127]. Selective blockers of SGLT2, and thus blocking ∼50% of renal glucose reabsorption, are in use and in further development for the treatment of diabetes (e.g. [113]).

Choline transporter

Overview

The high affinity, hemicholinium-3-sensitive, choline transporter (CHT) is expressed mainly in cholinergic neurones on nerve cell terminals and synaptic vesicles (keratinocytes being an additional location). In autonomic neurones, expression of CHT requires an activity-dependent retrograde signal from postsynaptic neurones [130]. Through recapture of choline generated by the hydrolysis of ACh by acetylcholinesterase, CHT serves to maintain acetylcholine synthesis within the presynaptic terminal [121]. 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 [120]. 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 [140].

NomenclatureCHT
Systematic nomenclatureSLC5A7
Common abbreviationCHT
HGNC, UniProtSLC5A7, Q9GZV3
Endogenous substratescholine
Substratestriethylcholine
Selective inhibitors (pIC50)hemicholinium-3 (pKi 8.3 – 9.0)
Radioligands (Kd)[3H]hemicholinium-3 (4x10-9 – 6x10-9 M)
StoichiometryNa+ : choline (variable stoichimetry); modulated by extracellular Cl- [128]

Comments

Ki and KD values for hemicholinium-3 listed in the table are for human CHT expressed in Xenopus laevis oocytes [133], or COS-7 cells [109]. hemicholinium mustard is a substrate for CHT that causes covalent modification and irreversible inactivation of the transporter. Several exogenous substances (e.g. triethylcholine) that are substrates for CHT act as precursors to cholinergic false transmitters.

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

Overview

The sodium-iodide symporter (NIS) is an iodide transporter found principally in the thyroid gland where it mediates the accumulation of I- within thyrocytes. Transport of I- by NIS from the blood across the basolateral membrane followed by apical efflux into the colloidal lumen, mediated at least in part by pendrin (SLC22A4), and most likely not SMCT1 (SLC5A8) as once thought, provides the I- required for the synthesis of the thyroid hormones triiodothyronine (T3) and thyroxine (T4) [111]. 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 [135]. 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 [122]. 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 [122]. SMCT1 is a high-affinity transporter whereas SMCT2 is a low-affinity transporter. The physiological substrates for SMCT1 and SMCT2 are lactate (L-lactic acid and D-lactic acid), pyruvic acid, propanoic acid, and nicotinic acid in non-colonic tissues such as the kidney. SMCT1 is also likely to be the principal transporter for the absorption of nicotinic acid (vitamin B3) in the intestine and kidney [124]. In the small intestine and colon, the physiological substrates for these transporters are nicotinic acid and the short-chain fatty acids acetic acid, propanoic acid, and butyric acid that are produced by bacterial fermentation of dietary fiber [132]. 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 [138]. SMCT1 also functions as a tumour suppressor in the colon as well as in various other non-colonic tissues [123]. The tumour-suppressive function of SMCT1 is based on its ability to transport pyruvic acid, an inhibitor of histone deacetylases, into cells in non-colonic tissues [139]; in the colon, the ability of SMCT1 to transport butyric acid and propanoic acid, also inhibitors of histone deacetylases, underlies the tumour-suppressive function of this transporter [122, 123, 125]. The ability of SMCT1 to promote histone acetylase inhibition through accumulation of butyric acid and propanoic acid in immune cells is also responsible for suppression of dendritic cell development in the colon [137].

NomenclatureNIS SMVT SMCT1 SMCT2
Systematic nomenclatureSLC5A5SLC5A6SLC5A8SLC5A12
Common abbreviationNISSMVTSMCT1SMCT2
HGNC, UniProtSLC5A5, Q92911 SLC5A6, Q9Y289 SLC5A8, Q8N695 SLC5A12, Q1EHB4
SubstratesNO3-, pertechnetate, perchlorate, thiocyanate, I-pantothenic acid [116], I- [116], biotin [116], lipoic acid [116]acetic acid, butyric acid, propanoic acid, nicotinic acid, β-D-hydroxybutyric acid, L-lactic acid, D-lactic acid, salicylic acid, 3-bromopyruvate, dichloroacetate, 2-oxothiazolidine-4-carboxylate, acetoacetic acid, benzoate, 5-aminosalicylate, α-ketoisocaproate, β-L-hydroxybutyric acid, pyroglutamic acid, γ-hydroxybutyric acid, pyruvic acid nicotinic acid, L-lactic acid, pyruvic acid
Inhibitors (pIC50)fenoprofen, ketoprofen, ibuprofen (4.2)
Stoichiometry2Na+ : 1 I- [119]; 1Na+ : 1 ClO4- [118]2Na+ : 1 biotin (or pantothenic acid) [134]2Na+ : 1 monocarboxylate [114]

Comments

I-, perchlorate, thiocyanate and NO3- are competitive substrate inhibitors of NIS [118]. lipoic acid appears to act as a competitive substrate inhibitor of SMVT [141] and the anticonvulsant drugs primidone and carbamazepine competitively block the transport of biotin by brush border vesicles prepared from human intestine [136].

Sodium myo-inositol cotransporter transporters

Overview

Three different mammalian myo-inositol cotransporters are currently known; two are the Na+-coupled SMIT1 and SMIT2 tabulated below and the third is proton-coupled HMIT (SLC2A13). SMIT1 and SMIT2 have a widespread and overlapping tissue location but in polarized cells, such as the Madin-Darby canine kidney cell line, they segregate to the basolateral and apical membranes, respectively [110]. 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 [108].

NomenclatureSMIT SGLT6
Systematic nomenclatureSLC5A3SLC5A11
Common abbreviationSMIT1SMIT2
HGNC, UniProtSLC5A3, P53794 SLC5A11, Q8WWX8
Substratesmyo-inositol, scyllo-inositol > L-fucose > L-xylose > L-glucose, D-glucose, α-methyl-D-glucopyranoside > D-galactose, D-fucose > D-xylose [126]myo-inositol = D-chiro-inositol> D-glucose > D-xylose > L-xylose [115]
Inhibitors (pIC50)phlorizin phlorizin
Stoichiometry2 Na+ :1 myo-inositol [126]2 Na+ :1 myo-inositol [112]

Comments

The data tabulated are those for dog SMIT1 and rabbit SMIT2. SMIT2 transports D-chiro-inositol, but SMIT1 does not. In addition, whereas SMIT1 transports both D-xylose and L-xylose and D-fucose and L-fucose , SMIT2 transports only the D-isomers of these sugars [115, 126]. 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 [131].

Further reading

Bailey CJ. (2011) Renal glucose reabsorption inhibitors to treat diabetes. Trends Pharmacol Sci 32: 6371. [PMID:21211857]

Chao EC, Henry RR. (2010) SGLT2 inhibition–a novel strategy for diabetes treatment. Nat Rev Drug Discov 9: 551559. [PMID:20508640]

Kinne RK, Castaneda F. (2011) SGLT inhibitors as new therapeutic tools in the treatment of diabetes. Handb Exp Pharmacol (203): 105126. [PMID:21484569]

Wright EM. (2013) Glucose transport families SLC5 and SLC50. Mol Aspects Med 34: 183196. [PMID:23506865]

Wright EM, Loo DD, Hirayama BA. (2011) Biology of human sodium glucose transporters. Physiol Rev 91: 733794. [PMID:21527736]

SLC6 neurotransmitter transporter family

Overview

Members of the solute carrier family 6 (SLC6) of sodium- and (sometimes chloride-) dependent neurotransmitter transporters [152, 156, 179] 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 [189]. The members of this superfamily share a structural motif of 10 TM segments that has been observed in crystal structures of the NSS bacterial homolog LeuTAa, a Na+-dependent amino acid transporter from Aquiflex aeolicus [206] and in several other transporter families structurally related to LeuT [164].

Monoamine transporter subfamily

Overview

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

NomenclatureNoradrenaline transporterDopamine transporter5HT transporter
Systematic nomenclatureSLC6A2SLC6A3SLC6A4
Common abbreviationNETDATSERT
HGNC, UniProtSLC6A2, P23975 SLC6A3, Q01959 SLC6A4, P31645
Endogenous substrates(-)-adrenaline, (-)-noradrenaline, dopamine (-)-adrenaline, (-)-noradrenaline, dopamine 5-HT
SubstratesMPP+, methamphetamine, amphetamine MPP+, methamphetamine, amphetamine MDMA, p-chloroamphetamine
Selective inhibitors (pIC50)mazindol (pKi 8.9), nisoxetine (pKi 8.4), nomifensine (pKi 8.1), reboxetine (pKi 8.0) [205]mazindol (pKi 8.0), WIN35428 (pKi 7.9), GBR12935 (pKi 7.6)paroxetine (pKi 9.6) [198], sertraline (pKi 9.1), fluoxetine (pKi 8.5) [198]
Radioligands (Kd)[3H]mazindol (5x10-10 M), [3H]nisoxetine (4x10-9 M)[3H]GBR12935 (3x10-9 M) [186], [3H]WIN35428 (1x10-8 M) [186][3H]paroxetine (2x10-10 M), [3H]citalopram (5x10-9 M)
Stoichiometry1 noradrenaline: 1 Na+:1 Cl- [171]1 dopamine: 1–2 Na+: 1 Cl- [170]1 5-HT:1 Na+:1 Cl- (in), + 1 K+ (out) [197]

Comments

[125I]RTI55 labels all three monoamine transporters (NET, DAT and SERT) with affinities between 0.5 and 5 nM. cocaine is an inhibitor of all three transporters with pKi values between 6.5 and 7.2. Potential alternative splicing sites in non-coding regions of SERT and NET have been identified. A bacterial homologue of SERT shows allosteric modulation by selected anti-depressants [194].

GABA transporter subfamily

Overview

The activity of GABA-transporters located predominantly upon neurones (GAT-1), glia (GAT-3) or both (GAT-2, BGT-1) serves to terminate phasic GABA-ergic transmission, maintain low ambient extracellular concentrations of GABA, and recycle GABA for reuse by neurones. Nonetheless, ambient concentrations of GABA are sufficient to sustain tonic inhibition mediated by high affinity GABAA receptors in certain neuronal populations [192]. 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 [181]. 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 [156, 172]. CT1, which transports creatine, has a ubiquitous expression pattern, often co-localizing with creatine kinase [156].

NomenclatureGAT1 GAT2 GAT3 BGT1 TauT CT1
Systematic nomenclatureSLC6A1SLC6A13SLC6A11SLC6A12SLC6A6SLC6A8
HGNC, UniProtSLC6A1, P30531 SLC6A13, Q9NSD5 SLC6A11, P48066 SLC6A12, P48065 SLC6A6, P31641 SLC6A8, P48029
Endogenous substratesGABA GABA, β-alanine GABA, β-alanine GABA, betaine GABA [145], β-alanine, taurine creatine
Substratesnipecotic acid, guvacine nipecotic acid, guvacine nipecotic acid, guvacine
Selective inhibitors (pIC50)SKF89976A (6.9), CI-966 (6.6), NNC-711 (5.9 – 6.9), tiagabine (5.6 – 7.0), LU32-176B (5.4), (R/S) EF-1500 (4.9 – 5.7), (R)-EF-1520 (5.05 – 5.4), (S)-EF-1520 (3.6 – 3.92)SNAP-5114 (5.2), SNAP-5114 (4.7)NNC052090 (5.6), (R/S) EF-1500 (4.9), (R)-EF-1520 (3.74 – 4.66), (S)-EF-1520 (3.6 – 4.47), LU32-176B (4.0)
Radioligands (Kd)[3H]tiagabine
Stoichiometry2Na+: 1Cl-: 1GABA2Na+: 1Cl-:1GABA≥ 2Na+: 2 Cl-: 1GABA3Na+: 1 (or 2) Cl-: 1GABA2Na+: 1Cl-: 1 taurineProbably 2Na+: 1Cl-: 1 creatine

Comments

The IC50 values for GAT1-4 reported in the table reflect the range reported in the literature from studies of both human and mouse transporters. There is a tendency towards lower IC50 values for the human orthologue [180]. SNAP-5114 is only weakly selective for GAT 2 and GAT3, with IC50 values in the range 22 to >30 μM at GAT1 and BGT1, whereas NNC052090 has at least an order of magnitude selectivity for BGT1 [see [157, 191] for reviews]. (R)-(1-{2-[tris(4-methoxyphenyl)methoxy]ethyl}pyrrolidin-2-yl)acetic acid is a recently described compound that displays 20-fold selectivity for GAT3 over GAT1 [165]. In addition to the inhibitors listed, EGYT3886 is a moderately potent, though non-selective, inhibitor of all cloned GABA transporters (IC50 = 26-46 μM; [160]). Diaryloxime and diarylvinyl ether derivatives of nipecotic acid and guvacine that potently inhibit the uptake of [3H]GABA into rat synaptosomes have been described [178]. 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 [157, 190] for reviews]. GAT3 is inhibited by physiologically relevant concentrations of Zn2+ [158]. 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 [161]. Although inhibitors of creatine transport by CT1 (e.g. β-guanidinopropionic acid, cyclocreatine, guanidinoethane sulfonic acid) are known (e.g. [159]) they insufficiently characterized to be included in the table.

Glycine transporter subfamily

Overview

Two gene products, GlyT1 and GlyT2, are known that give rise to transporters that are predominantly located on glia and neurones, respectively. Five variants of GlyT1 (a,b,c,d & e) differing in their N- and C-termini are generated by alternative promoter usage and splicing, and three splice variants of GlyT2 (a,b & c) have also been identified (see [148, 163, 167, 196] for reviews). GlyT1 transporter isoforms expressed in glia surrounding glutamatergic synapses regulate synaptic glycine concentrations influencing NMDA receptor-mediated neurotransmission [147, 166], but also are important, in early neonatal life, for regulating glycine concentrations at inhibitory glycinergic synapses [168]. 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 [168, 199]. 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 [207]. 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 [169, 188]. Mice in which GlyT2 has been deleted develop a fatal hyperekplexia phenotype during the second postnatal week [169] and mutations in the human gene encoding GlyT2 (SLC6A5) have been identified in patients with hyperekplexia (reviewed by [173]). ATB0+ (SLCA14) is a transporter for numerous dipolar and cationic amino acids and thus has a much broader substrate specificity than the glycine transporters alongside which it is grouped on the basis of structural similarity [156]. ATB0+ is expressed in various peripheral tissues [156]. 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.

NomenclatureGlycine transporter 1Glycine transporter 2ATB0,+ Proline transporter
Systematic nomenclatureSLC6A9SLC6A5SLC6A14SLC6A7
Common abbreviationGlyT1GlyT2ATB0,+PROT
HGNC, UniProtSLC6A9, P48067 SLC6A5, Q9Y345 SLC6A14, Q9UN76 SLC6A7, Q99884
Endogenous substratesglycine, sarcosine glycine L-isoleucine > L-leucine, L-methionine > L-phenylalanine > L-tryptophan > L-valine > L-serine [195], β-alanine [144, 145]L-proline
Substrates1-methyltryptophan [177], BCH , valganciclovir [200], zwitterionic or cationic NOS inhibitors [174]
Selective inhibitors (pIC50)(R)-NFPS (8.5 – 9.1), SSR-103800 (8.7), N-methyl-SSR504734 (8.6), LY2365109 (7.8), GSK931145 (7.6)ALX 1393, ALX 1405, Org 25543 (7.7)α-methyl-D,L-tryptophan (3.6) [177]LP-403812 (7.0) [208]
Radioligands (Kd)[3H](R)-NPTS (1x10-9 M), [3H]GSK931145 (1.7x10-9 M), [35S]ACPPB (2x10-9 M), [3H]SB-733993 (2.2x10-9 M), [3H]N-methyl-SSR504734 (3.3x10-9 – 8.1x10-9 M), [3H]NFPS (7x10-9 – 2.1x10-8 M)
Stoichiometry2 Na+: 1 Cl-: 1 glycine3 Na+: 1 Cl-: 1 glycine2-3 Na+: 1 Cl-: 1 amino acid [195]Probably 2 Na+: 1 Cl-: 1 L-proline
CommentN-Oleoyl-L-carnitine (0.3μM, [155]) and and N-arachidonoylglycine (IC50 5-8 μM, [204]) have been described as potential endogenous selective GlyT2 inhibitors

Comments

sarcosine is a selective transportable inhibitor of GlyT1 and also a weak agonist at the glycine binding site of the NMDA receptor [210], but has no effect on GlyT2. This difference has been attributed to a single glycine residue in TM6 (serine residue in GlyT2) [202]. Inhibition of GLYT1 by the sarcosine derivatives NFPS, NPTS and Org 24598 is non-competitive [182, 183]. IC50 values for Org 24598 reported in the literature vary, most likely due to differences in assay conditions [149, 182]. The tricyclic antidepressant amoxapine weakly inhibits GlyT2 (IC50 92 μM) with approximately 10-fold selectivity over GlyT1 [184]. The endogenous lipids arachidonic acid and anandamide exert opposing effects upon GlyT1a, inhibiting (IC50 ∼ 2 μM) and potentiating (EC50 ∼ 13 μM) transport currents, respectively [185]. 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 [162, 175, 204]. Protons [146] and Zn2+ [176] act as non-competitive inhibitors of GlyT1b, with IC50 values of ∼100 nM and ∼10 μM respectively, but neither ion affects GlyT2 (reviewed by [201]). Glycine transport by GLYT1 is inhibited by lithium, whereas GLYT2 transport is stimulated (both in the presence of Na+) [187].

Neutral amino acid transporter subfamily

Overview

Certain members of neutral amino acid transport family are expressed upon the apical surface of epithelial cells and are important for the absorption of amino acids from the duodenum, jejunum and ileum and their reabsorption within the proximal tubule of the nephron (i.e. B0AT1 (SLC6A19), SLC6A17, SLC6A18, SLC6A20). Others may function as transporters for neurotransmitters or their precursors (i.e. B0AT2, SLC6A17) [153].

NomenclatureB0AT1 B0AT2 B0AT3 NTT5 NTT4 SIT1
Systematic nomenclatureSLC6A19SLC6A15SLC6A18SLC6A16SLC6A17SLC6A20
HGNC, UniProtSLC6A19, Q695T7 SLC6A15, Q9H2J7 SLC6A18, Q96N87 SLC6A16, Q9GZN6 SLC6A17, Q9H1V8 SLC6A20, Q9NP91
Endogenous substratesL-leucine, L-methionine, L-isoleucine, L-valine > L-asparagine, L-phenylalanine, L-alanine, L-serine > L-threonine, glycine, L-proline [152]L-proline > L-alanine, L-valine, L-methionine, L-leucine > L-isoleucine, L-threonine, L-asparagine, L-serine, L-phenylalanine > glycine [152]L-alanine, glycine > L-methionine, L-phenylalanine, L-leucine, L-histidine, L-glutamine [203]L-leucine, L-methionine, L-proline > L-cysteine, L-alanine, L-glutamine, L-serine > L-histidine, glycine [209]L-proline
Stoichiometry1 Na+: 1 amino acid [154]1 Na+: 1 amino acid [151]Na+- and Cl- -dependent transport [193]Na+-dependent, Cl--independent transport [209]2 Na+: 1 Cl-: 1 imino acid [150]
CommentMutations in B0AT1 are associated with Hartnup disorder

Further reading

Bröer S, Gether U. (2012) The solute carrier 6 family of transporters. Br J Pharmacol 167: 256278. [PMID:22519513]

Pramod AB, Foster J, Carvelli L, Henry LK. (2013) SLC6 transporters: structure, function, regulation, disease association and therapeutics. Mol Aspects Med 34: 197219. [PMID:23506866]

Ramamoorthy S, Shippenberg TS, Jayanthi LD. (2011) Regulation of monoamine transporters: Role of transporter phosphorylation. Pharmacol Ther 129: 220238. [PMID:20951731]

Rudnick G. (2011) Cytoplasmic permeation pathway of neurotransmitter transporters. Biochemistry 50: 74627475. [PMID:21774491]

Zhong H, Sánchez C, Caron MG. (2012) Consideration of allosterism and interacting proteins in the physiological functions of the serotonin transporter. Biochem Pharmacol 83: 435442. [PMID:21983034]

SLC8 family of sodium/calcium exchangers

Overview

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

NomenclatureSodium/calcium exchanger 1 Sodium/calcium exchanger 2 Sodium/calcium exchanger 3
Systematic nomenclatureSLC8A1SLC8A2SLC8A3
Common abbreviationNCX1NCX2NCX3
HGNC, UniProtSLC8A1, P32418 SLC8A2, Q9UPR5 SLC8A3, P57103
Stoichiometry3 Na+ (in) : 1 Ca2+ (out) or 4 Na+ (in) : 1 Ca2+ (out) [211]; Reverse mode 1 Ca2+ (in): 1 Na+ (out)

Comments

Although subtype-selective inhibitors of NCX function are not widely available, 3,4–dichlorobenzamil and CBDMB act as non-selective NCX inhibitors, while SEA0400, KB-R7943, SN6 and ORM-10103 [212] act to inhibit NCX function selectively.

Further reading

Annunziato L, Pignataro G, Di Renzo GF. (2004) Pharmacology of brain Na+/Ca2+ exchanger: from molecular biology to therapeutic perspectives. Pharmacol Rev 56: 633654. [PMID:15602012]

Gabellini N. (2004) Transcriptional regulation by cAMP and Ca2+ links the Na+/Ca2+ exchanger 3 to memory and sensory pathways. Mol Neurobiol 30: 91116. [PMID:15247490]

Lytton J. (2007) Na+/Ca2+ exchangers: three mammalian gene families control Ca2+ transport. Biochem J 406: 365382. [PMID:17716241]

Quednau BD, Nicoll DA, Philipson KD. (2004) The sodium/calcium exchanger family-SLC8. Pflugers Arch 447: 543548. [PMID:12734757]

Watanabe Y, Koide Y, Kimura J. (2006) Topics on the Na+/Ca2+ exchanger: pharmacological characterization of Na+/Ca2+ exchanger inhibitors. J Pharmacol Sci 102: 716. [PMID:16990699]

Zhang YH, Hancox JC. (2009) Regulation of cardiac Na+-Ca2+ exchanger activity by protein kinase phosphorylation–still a paradox?. Cell Calcium 45: 110. [PMID:18614228]

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 [215-217]. Li+ and NH4+, but not K+, ions may also be transported by some isoforms. Modelling of the topology of these transporters indicates 12 TM regions with an extended intracellular C-terminus containing multiple regulatory sites.

NHE1 is considered to be a ubiquitously-expressed ‘housekeeping’ transporter. NHE3 is highly expressed in the intestine and kidneys and regulate sodium movements in those tissues. NHE10 is present in sperm [220] and osteoclasts [214]; gene disruption results in infertile male mice [220].

Comments

Analogues of the non-selective cation transport inhibitor amiloride appear to inhibit NHE function through competitive inhibition of the extracellular Na+ binding site. The more selective amiloride analogues MPA and EIPA exhibit a rank order of affinity of inhibition of NHE1 > NHE2 > NHE3 [213, 218, 219].

Further reading

Bobulescu IA, Moe OW. (2009) Luminal Na(+)/H (+) exchange in the proximal tubule. Pflugers Arch 458: 521. [PMID:18853182]

Casey JR, Grinstein S, Orlowski J. (2010) Sensors and regulators of intracellular pH. Nat Rev Mol Cell Biol 11: 5061. [PMID:19997129]

Donowitz M, Ming Tse C, Fuster D. (2013) SLC9/NHE gene family, a plasma membrane and organellar family of Na+/H+ exchangers. Mol Aspects Med 34: 236251. [PMID:23506868]

Kato A, Romero MF. (2011) Regulation of electroneutral NaCl absorption by the small intestine. Annu Rev Physiol 73: 261281. [PMID:21054167]

Kemp G, Young H, Fliegel L. (2008) Structure and function of the human Na+/H+ exchanger isoform 1. Channels (Austin) 2: 329336. [PMID:19001864]

Ohgaki R, van IJzendoorn SC, Matsushita M, Hoekstra D, Kanazawa H. (2011) Organellar Na+/H+ exchangers: novel players in organelle pH regulation and their emerging functions. Biochemistry 50: 443450. [PMID:21171650]

SLC10 family of sodium-bile acid co-transporters

Overview

The SLC10 family transport bile acids, sulphated solutes, and other xenobiotics in a sodium-dependent manner. The founding members, SLC10A1 (NTCP) and SLC10A2 (ASBT) function, along with members of the ABC transporter family (MDR1/ABCB1, BSEP/ABCB11 and MRP2/ABCC2) and the organic solute transporter obligate heterodimer OSTα:OSTβ (SLC51), to maintain the enterohepatic circulation of bile acids [225, 234]. SLC10A6 (SOAT) functions as a sodium-dependent transporter of sulphated solutes included sulfphated steroids and bile acids [228, 230]. Transport function has not yet been demonstrated for the 4 remaining members of the SLC10 family, SLC10A3 (P3), SLC10A4 (P4), SLC10A5 (P5), and SLC10A7 (P7), and the identity of their endogenous substrates remain unknown [227, 230, 231, 237]. Members of the SLC10 family are predicted to have seven transmembrane domains with an extracellular N-terminus and cytoplasmic C-terminus [221, 232].

NomenclatureSodium/bile acid and sulphated solute cotransporter 1 Sodium/bile acid and sulphated solute cotransporter 2 Sodium/bile acid and sulphated solute cotransporter 6
Systematic nomenclatureSLC10A1SLC10A2SLC10A6
Common abbreviationNTCPASBTSOAT
HGNC, UniProtSLC10A1, Q14973 SLC10A2, Q12908 SLC10A6, Q3KNW5
Substratestauroursodeoxycholic acid, taurocholic acid, taurochenodeoxycholic acid > GCA > cholic acid [235]GDCA > GUDCA, GCDA > taurocholic acid > cholic acid [224]pregnenolone sulphate [228], dehydroepiandrosterone sulphate [230], taurolithocholic acid-3-sulphate, estrone-3-sulphate
Endogenous substratesT3, dehydroepiandrosterone sulphate [224, 227, 235], estrone-3-sulphate, iodothyronine sulphates
Radioligands (Kd)[3H]taurocholic acid [224]
Stoichiometry2 Na+: 1 bile acid [221, 228]>1 Na+: 1 bile acid [224, 238]
Commentchenodeoxycholyl-Nε-nitrobenzoxadiazol-lysine is a fluorescent bile acid analogue used as a probe [229].
Inhibitors (pIC50)cyclosporin A [226, 233], irbesartan [226], propranolol [224]SC-435 (8.82) [222], 264W94 (7.32) [236, 239]

Comments

Heterologously expressed SLC10A4 [229] or SLC10A7 [231] failed to exhibit significant transport of taurocholic acid, pregnenolone sulphate, DHEAS or choline. SLC10A4 has recently been suggested to associate with neuronal vesicles [223].

Further reading

Borges K. (2013) Slc10A4 - what do we know about the function of this "secret ligand carrier" protein?. Exp Neurol 248C: 258261 [Epub ahead of print]. [PMID:23810836]

Claro da Silva T, Polli JE, Swaan PW. (2013) The solute carrier family 10 (SLC10): beyond bile acid transport. Mol Aspects Med 34: 252269. [PMID:23506869]

Dawson PA, Lan T, Rao A. (2009) Bile acid transporters. J Lipid Res 50: 23402357. [PMID:19498215]

Döring B, Lütteke T, Geyer J, Petzinger E. (2012) The SLC10 carrier family: transport functions and molecular structure. Curr Top Membr 70: 105168. [PMID:23177985]

Zwicker BL, Agellon LB. (2013) Transport and biological activities of bile acids. Int J Biochem Cell Biol 45: 13891398. [PMID:23603607]

SLC11 family of proton-coupled metal ion transporters

Overview

The family of proton-coupled metal ion transporters are responsible for movements of divalent cations, particularly ferrous and manganese ions, across the cell membrane (SLC11A2/DMT1) and across endosomal (SLC11A2/DMT1) or lysosomal/phagosomal membranes (SLC11A1/NRAMP1), dependent on proton transport. Both proteins appear to have 12 TM regions and cytoplasmic N- and C- termini. NRAMP1 is involved in antimicrobial action in macrophages, although its precise mechanism is undefined. Facilitated diffusion of divalent cations into phagosomes may increase intravesicular free radicals to damage the pathogen. Alternatively, export of divalent cations from the phagosome may deprive the pathogen of essential enzyme cofactors. SLC11A1/DMT1 is more widely expressed and appears to assist in divalent cation assimilation from the diet, as well as in phagocytotic cells.

NomenclatureNRAMP1 DMT1
Systematic nomenclatureSLC11A1SLC11A2
HGNC, UniProtSLC11A1, P49279 SLC11A2, P49281
Endogenous substratesFe2+, Mn2+Cd2+, Co2+, Cu2+, Fe2+, Mn2+
Stoichiometry1 H+ : 1 Fe2+ (out) or 1 Fe2+ (in) : 1 H+ (out)1 H+ : 1 Fe2+ (out) [240]

Comments

Loss-of-function mutations in NRAMP1 are associated with increased susceptibility to microbial infection (OMIM: 607948). Loss-of-function mutations in DMT1 are associated with microcytic anemia (OMIM: 206100).

Further reading

Li X, Yang Y, Zhou F, Zhang Y, Lu H, Jin Q, Gao L. (2011) SLC11A1 (NRAMP1) polymorphisms and tuberculosis susceptibility: updated systematic review and meta-analysis. PLoS ONE 6: e15831. [PMID:21283567]

Mackenzie B, Hediger MA. (2004) SLC11 family of H+-coupled metal-ion transporters NRAMP1 and DMT1. Pflugers Arch 447: 571579. [PMID:14530973]

Montalbetti N, Simonin A, Kovacs G, Hediger MA. (2013) Mammalian iron transporters: families SLC11 and SLC40. Mol Aspects Med 34: 270287. [PMID:23506870]

Nevo Y, Nelson N. (2006) The NRAMP family of metal-ion transporters. Biochim Biophys Acta 1763: 609620. [PMID:16908340]

Zheng W, Monnot AD. (2012) Regulation of brain iron and copper homeostasis by brain barrier systems: implication in neurodegenerative diseases. Pharmacol Ther 133: 177188. [PMID:22115751]

SLC12 family of cation-coupled chloride transporters

Overview

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

NomenclatureKidney-specific Na-K-Cl symporter Basolateral Na-K-Cl symporter Na-Cl symporter
Systematic nomenclatureSLC12A1SLC12A2SLC12A3
Common abbreviationNKCC2NKCC1NCC
HGNC, UniProtSLC12A1, Q13621 SLC12A2, P55011 SLC12A3, P55017
Inhibitors (pIC50)bumetanide [242], furosemide [242], piretanide [242]bumetanide [242], furosemide [242], piretanide [242]chlorothiazide, hydrochlorothiazide, metolazone
Stoichiometry1 Na+ : 1 K+ : 2 Cl- (in)1 Na+ : 1 K+ : 2 Cl- (in)1 Na+ : 1 Cl- (in)
NomenclatureK-Cl cotransporter 1 K-Cl cotransporter 2 K-Cl cotransporter 3 K-Cl cotransporter 4
Systematic nomenclatureSLC12A4SLC12A5SLC12A6SLC12A7
Common abbreviationKCC1KCC2KCC3KCC4
HGNC, UniProtSLC12A4, Q9UP95 SLC12A5, Q9H2X9 SLC12A6, Q9UHW9 SLC12A7, Q9Y666
Inhibitors (pIC50)DIOA DIOA, VU0240551 [241]DIOA DIOA
Stoichiometry1 K+ : 1 Cl- (out)1 K+ : 1 Cl- (out)1 K+ : 1 Cl- (out)1 K+ : 1 Cl- (out)
NomenclatureCation-chloride cotransporter 9 Cation-chloride cotransporter 6
Systematic nomenclatureSLC12A8SLC12A9
Common abbreviationCCC9CCC6
HGNC, UniProtSLC12A8, A0AV02 SLC12A9, Q9BXP2
Substratesspermine, L-glutamic acid, spermidine, L-aspartic acid
StoichiometryUnknown
CommentCCC6 is regarded as an orphan transporter

Comments

DIOA is able to differentiate KCC isoforms from NKCC and NCC transporters, but also inhibits CFTR [243].

Further reading

Arroyo JP, Kahle KT, Gamba G. (2013) The SLC12 family of electroneutral cation-coupled chloride cotransporters. Mol Aspects Med 34: 288298. [PMID:23506871]

Gagnon KB, Delpire E. (2013) Physiology of SLC12 transporters: lessons from inherited human genetic mutations and genetically engineered mouse knockouts. Am J Physiol, Cell Physiol 304: C693C714. [PMID:23325410]

Gamba G, Friedman PA. (2009) Thick ascending limb: the Na(+):K (+):2Cl (-) co-transporter, NKCC2, and the calcium-sensing receptor, CaSR. Pflugers Arch 458: 6176. [PMID:18982348]

Hebert SC, Mount DB, Gamba G. (2004) Molecular physiology of cation-coupled Cl- cotransport: the SLC12 family. Pflugers Arch 447: 580593. [PMID:12739168]

Kahle KT, Rinehart J, Lifton RP. (2010) Phosphoregulation of the Na-K-2Cl and K-Cl cotransporters by the WNK kinases. Biochim Biophys Acta 1802: 11501158. [PMID:20637866]

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 Physiol 293: C1187C1208. [PMID:17670895]

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.

NomenclatureNa+/sulfate cotransporter Na+/dicarboxylate cotransporter 1 Na+/dicarboxylate cotransporter 3 Na+/sulfate cotransporter Na+/citrate cotransporter
Systematic nomenclatureSLC13A1SLC13A2SLC13A3SLC13A4SLC13A5
Common abbreviationNaS1NaC1NaC3NaS2NaC2
HGNC, UniProtSLC13A1, Q9BZW2 SLC13A2, Q13183 SLC13A3, Q8WWT9 SLC13A4, Q9UKG4 SLC13A5, Q86YT5
Endogenous substratesSeO42-, S2O32-, SO42- citric acid, succinic acid citric acid, succinic acid SO42- citric acid, pyruvic acid
Stoichiometry3 Na+ : 1 SO42- (in)3 Na+ : 1 dicarboxylate2- (in)Unknown3 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 Biol 37: 13501356. [PMID:15833267]

Markovich D. (2011) Physiological roles of renal anion transporters NaS1 and Sat1. Am J Physiol Renal Physiol 300: F1267F1270. [PMID:21490138]

Markovich D, Aronson PS. (2007) Specificity and regulation of renal sulfate transporters. Annu Rev Physiol 69: 361375. [PMID:17002596]

Markovich D, Murer H. (2004) The SLC13 gene family of sodium sulphate/carboxylate cotransporters. Pflugers Arch 447: 594602. [PMID:12915942]

SLC14 family of facilitative urea transporters

Overview

As a product of protein catabolism, urea is moved around the body and through the kidneys for excretion. Although there is experimental evidence for concentrative urea transporters, these have not been defined at the molecular level. The SLC14 family are facilitative transporters, allowing urea movement down its concentration gradient. Multiple splice variants of these transporters have been identified; for UT-A transporters, in particular, there is evidence for cell-specific expression of these variants with functional impact [245]. 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.

NomenclatureErythrocyte urea transporter Kidney urea transporter
Systematic nomenclatureSLC14A1SLC14A2
Common abbreviationUT-BUT-A
HGNC, UniProtSLC14A1, Q13336 SLC14A2, Q15849
Endogenous substratesammonium carbonate [246], urea [246], formamide [246]urea [244]
Substratesacrylamide [246], acetamide [246], methylurea [246]
StoichiometryEquilibrativeEquilibrative

Further reading

Pannabecker TL. (2013) Comparative physiology and architecture associated with the mammalian urine concentrating mechanism: role of inner medullary water and urea transport pathways in the rodent medulla. Am J Physiol Regul Integr Comp Physiol 304: R488R503. [PMID:23364530]

Shayakul C, Clémençon B, Hediger MA. (2013) The urea transporter family (SLC14): physiological, pathological and structural aspects. Mol Aspects Med 34: 313322. [PMID:23506873]

Shayakul C, Hediger MA. (2004) The SLC14 gene family of urea transporters. Pflugers Arch 447: 603609. [PMID:12856182]

Smith CP. (2009) Mammalian urea transporters. Exp Physiol 94: 180185. [PMID:19028811]

Stewart G. (2011) The emerging physiological roles of the SLC14A family of urea transporters. Br J Pharmacol 164: 17801792. [PMID:21449978]

SLC15 family of peptide transporters

Overview

The SLC15 family of peptide transporters may be divided on the basis of structural and functional differences into two subfamilies: SLC15A1 (PepT1) and SLC15A2 (PepT2) transport di- and tripeptides, but not amino acids, whereas SLC15A3 (PHT2) and SLC15A4 (PHT1) transport L-histidine and some di- and tripeptides [251]. The transporters are 12 TM proteins with intracellular termini and an extended extracellular loop at TM 9/10. The crystal structure of PepTSo (a prokaryote homologue of PepT1 and PepT2 from Shewanella oneidensis) confirms many of the predicted structural features of mammalian PepT1 and PepT2 [261].

PHT1 has been suggested to be intracellular [262], while PHT2 protein is located on lysosomes in transfected cells [250, 257, 264]. 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 [259]. 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 [249, 265].

NomenclaturePeptide transporter 1 Peptide transporter 2 Peptide transporter 3 Peptide transporter 4
Systematic nomenclatureSLC15A1SLC15A2SLC15A3SLC15A4
Common abbreviationPepT1PepT2PHT2PHT1
HGNC, UniProtSLC15A1, P46059 SLC15A2, Q16348 SLC15A3, Q8IY34 SLC15A4, Q8N697
Endogenous substrates5-aminolevulinic acid [253], dipeptides [253], tripeptides [253]5-aminolevulinic acid, dipeptides, tripeptidesL-histidine, carnosine, dipeptides, tripeptidesL-histidine, carnosine, dipeptides, tripeptides
SubstratesfMet-Leu-Phe [260], cyclacillin [254], valacyclovir [255], cefadroxil [254], muramyl dipeptide [268]cyclacillin [254], cefadroxil [254]valacyclovir [247]
Inhibitors (pIC50)4-AMBA [252], Lys[Z(NO2)]-Pro [258]Lys[Z(NO2)]-Lys[Z(NO2)] [248, 267], Lys[Z(NO2)]-Pro
Radioligands (Kd)[11C]GlySar, [14C]GlySar, [3H]GlySar [11C]GlySar, [14C]GlySar, [3H]GlySar [14C]histidine, [3H]histidine [14C]histidine, [3H]histidine
Stoichiometry1 H+ : 1 zwitterionic peptide (in)2 H+ : 1 zwitterionic peptide (in)UnknownUnknown

Comments

The PepT1 and PepT2 transporters are particularly promiscuous in the transport of dipeptides and tripeptides from the endogenous amino acids, as well as some D-amino acid containing peptides. PepT1 has also been exploited to allow delivery of therapeutic pro-drugs, such as those for zidovudine [256], sulpiride [269] and cytarabine [266].

D-Ala-Lys-AMCA has been used as a fluorescent probe to identify transport via both PepT1 and PepT2 [263].

Further reading

Anderson CM, Thwaites DT. (2010) Hijacking solute carriers for proton-coupled drug transport. Physiol (Bethesda) 25: 364377. [PMID:21186281]

Biegel A, Knütter I, Hartrodt B, Gebauer S, Theis S, Luckner P, Kottra G, Rastetter M, Zebisch K, Thondorf I et al. (2006) The renal type H+/peptide symporter PEPT2: structure-affinity relationships. Amino Acids 31: 137156. [PMID:16868651]

Brandsch M. (2009) Transport of drugs by proton-coupled peptide transporters: pearls and pitfalls. Expert Opin Drug Metab Toxicol 5: 887905. [PMID:19519280]

Ingersoll SA, Ayyadurai S, Charania MA, Laroui H, Yan Y, Merlin D. (2012) The role and pathophysiological relevance of membrane transporter PepT1 in intestinal inflammation and inflammatory bowel disease. Am J Physiol Gastrointest Liver Physiol 302: G484G492. [PMID:22194420]

Smith DE, Clémençon B, Hediger MA. (2013) Proton-coupled oligopeptide transporter family SLC15: physiological, pharmacological and pathological implications. Mol Aspects Med 34: 323336. [PMID:23506874]

Thwaites DT, Anderson CM. (2007) H+-coupled nutrient, micronutrient and drug transporters in the mammalian small intestine. Exp Physiol 92: 603619. [PMID:17468205]

SLC16 family of monocarboxylate transporters

Overview

Members of the SLC16 family may be divided into subfamilies on the basis of substrate selectivities, particularly lactate (e.g. L-lactic acid), pyruvic acid and ketone bodies, as well as aromatic amino acids. Topology modelling suggests 12 TM domains, with intracellular termini and an extended loop at TM 6/7.

The proton-coupled monocarboxylate transporters (monocarboxylate transporters 1, 4, 2 and 3) allow transport of the products of cellular metabolism, principally lactate (e.g. L-lactic acid) and pyruvic acid.

NomenclatureMonocarboxylate transporter 1 Monocarboxylate transporter 4 Monocarboxylate transporter 2 Monocarboxylate transporter 3
Systematic nomenclatureSLC16A1SLC16A3SLC16A7SLC16A8
Common abbreviationMCT1MCT4MCT2MCT3
HGNC, UniProtSLC16A1, P53985 SLC16A3, O15427 SLC16A7, O60669 SLC16A8, O95907
Endogenous substratesβ-D-hydroxybutyric acid, L-lactic acid, pyruvic acid L-lactic acid, pyruvic acid L-lactic acid, pyruvic acid L-lactic acid
Substratesγ-hydroxybutyric acid [272]
Stoichiometry1 H+: 1 monocarboxylate- (out)1 H+: 1 monocarboxylate- (out)1 H+: 1 monocarboxylate- (out)1 H+: 1 monocarboxylate- (out)
NomenclatureMonocarboxylate transporter 8 Monocarboxylate transporter 10
Systematic nomenclatureSLC16A2SLC16A10
Common abbreviationMCT8TAT1
HGNC, UniProtSLC16A2, P36021 SLC16A10, Q8TF71
Endogenous substratesT3 [270], T4 [270]L-tryptophan, L-phenylalanine, L-DOPA, L-tyrosine
StoichiometryUnknownUnknown
NomenclatureMonocarboxylate transporter 5 Monocarboxylate transporter 6 Monocarboxylate transporter 7 Monocarboxylate transporter 9 Monocarboxylate transporter 11 Monocarboxylate transporter 12 Monocarboxylate transporter 13 Monocarboxylate transporter 14
Systematic nomenclatureSLC16A4SLC16A5SLC16A6SLC16A9SLC16A11SLC16A12SLC16A13SLC16A14
Common abbreviationMCT5MCT6MCT7MCT9MCT11MCT12MCT13MCT14
HGNC, UniProtSLC16A4, O15374 SLC16A5, O15375 SLC16A6, O15403 SLC16A9, Q7RTY1 SLC16A11, Q8NCK7 SLC16A12, Q6ZSM3 SLC16A13, Q7RTY0 SLC16A14, Q7RTX9
StoichiometryUnknownUnknownUnknownUnknownUnknownUnknownUnknownUnknown
CommentMCT6 has been reported to transport bumetanide, but not short chain fatty acids [271]

Comments

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

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

Further reading

Anderson CM, Thwaites DT. (2010) Hijacking solute carriers for proton-coupled drug transport. Physiology (Bethesda) 25: 364377. [PMID:21186281]

Braun D, Wirth EK, Schweizer U. (2010) Thyroid hormone transporters in the brain. Rev Neurosci 21: 173186. [PMID:20879691]

Friesema EC, Visser WE, Visser TJ. (2010) Genetics and phenomics of thyroid hormone transport by MCT8. Mol Cell Endocrinol 322: 107113. [PMID:20083155]

Halestrap AP, Meredith D. (2004) The SLC16 gene family-from monocarboxylate transporters (MCTs) to aromatic amino acid transporters and beyond. Pflugers Arch 447: 619628. [PMID:12739169]

Heuer H, Visser TJ. (2009) Minireview: Pathophysiological importance of thyroid hormone transporters. Endocrinology 150: 10781083. [PMID:19179441]

Jansen J, Friesema EC, Milici C, Visser TJ. (2005) Thyroid hormone transporters in health and disease. Thyroid 15: 757768. [PMID:16131319]

Meredith D, Christian HC. (2008) The SLC16 monocaboxylate transporter family. Xenobiotica 38: 10721106. [PMID:18668440]

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 gamma-hydroxybutyric acid. AAPS J 10: 311321. [PMID:18523892]

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 Endocrinol 44: 111. [PMID:19541799]

Visser TJ. (2007) Thyroid hormone transporters. Horm Res 68 Suppl 5: 2830. [PMID:18174701]

Visser WE, Friesema EC, Jansen J, Visser TJ. (2008) Thyroid hormone transport in and out of cells. Trends Endocrinol Metab 19: 5056. [PMID:18291666]

SLC17 phosphate and organic anion transporter family

Overview

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

Type I sodium-phosphate co-transporters

Overview

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

NomenclatureSodium/phosphate cotransporter 1 Sodium/phosphate cotransporter 3 Sodium/phosphate cotransporter 4 Sodium/phosphate cotransporter homolog
Systematic nomenclatureSLC17A1SLC17A2SLC17A3SLC17A4
Common abbreviationNPT1NPT3NPT4
HGNC, UniProtSLC17A1, Q14916 SLC17A2, O00624 SLC17A3, O00476 SLC17A4, Q9Y2C5
SubstratesCl- [275], probenecid [274], PO34- [275], uric acid [275], penicillin G [274], organic acids [275]
StoichiometryUnknownUnknownUnknownUnknown

Sialic acid transporter

Overview

The sialic acid transporter is expressed on both lysosomes and synaptic vesicles, where it appears to allow export of sialic acid and accumulation of acidic amino acids, respectively [277], driven by proton gradients. In lysosomes, degradation of glycoproteins generates amino acids and sugar residues, which are metabolized further following export from the lysosome.

NomenclatureSialin
Systematic nomenclatureSLC17A5
Common abbreviationAST
HGNC, UniProtSLC17A5, Q9NRA2
Endogenous substratesL-glutamic acid (in) [277], L-lactic acid, L-aspartic acid [277], gluconate (out), sialic acid, glucuronic acid
Stoichiometry1 H+: 1 sialic acid (out)

Comments

Loss-of-function mutations in sialin are associated with Salla disease (OMIM: 604369), an autosomal recessive neurodegenerative disorder associated with sialic acid storage disease [279].

Vesicular glutamate transporters (VGLUTs)

Overview

Vesicular glutamate transporters (VGLUTs) allow accumulation of glutamate into synaptic vesicles, as well as secretory vesicles in endocrine tissues. The roles of VGLUTs in kidney and liver are unclear. These transporters appear to utilize the proton gradient and also express a chloride conductance [273].

NomenclatureVesicular glutamate transporter 1 Vesicular glutamate transporter 2 Vesicular glutamate transporter 3
Systematic nomenclatureSLC17A7SLC17A6SLC17A8
Common abbreviationVGLUT1VGLUT2VGLUT3
HGNC, UniProtSLC17A7, Q9P2U7 SLC17A6, Q9P2U8 SLC17A8, Q8NDX2
Endogenous substratesL-glutamic acid > D-glutamic acid L-glutamic acid > D-glutamic acid L-glutamic acid > D-glutamic acid
StoichiometryUnknownUnknownUnknown

Comments

Endogenous ketoacids produced during fasting have been proposed to regulate VGLUT function through blocking chloride ion-mediated allosteric enhancement of transporter function [276].

Vesicular nucleotide transporter

Overview

The vesicular nucleotide transporter is the most recent member of the SLC17 family to have an assigned function. Uptake of ATP was independent of pH, but dependent on chloride ions and membrane potential [278].

NomenclatureVesicular nucleotide transporter
Systematic nomenclatureSLC17A9
Common abbreviationVNUT
HGNC, UniProtSLC17A9, Q9BYT1
Endogenous substratesATP [278], GTP [278], GDP [278]
StoichiometryUnknown

Comments

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

Further reading

Biber J, Hernando N, Forster I. (2013) Phosphate transporters and their function. Annu Rev Physiol 75: 535550. [PMID:23398154]

El Mestikawy S, Wallén-Mackenzie A, Fortin GM, Descarries L, Trudeau LE. (2011) From glutamate co-release to vesicular synergy: vesicular glutamate transporters. Nat Rev Neurosci 12: 204216. [PMID:21415847]

Marks J, Debnam ES, Unwin RJ. (2010) Phosphate homeostasis and the renal-gastrointestinal axis. Am J Physiol Renal Physiol 299: F285F296. [PMID:20534868]

Miyamoto K, Haito-Sugino S, Kuwahara S, Ohi A, Nomura K, Ito M, Kuwahata M, Kido S, Tatsumi S, Kaneko I et al. (2011) Sodium-dependent phosphate cotransporters: lessons from gene knockout and mutation studies. J Pharm Sci 100: 37193730. [PMID:21567407]

Omote H, Miyaji T, Juge N, Moriyama Y. (2011) Vesicular neurotransmitter transporter: bioenergetics and regulation of glutamate transport. Biochemistry 50: 55585565. [PMID:21612282]

Reimer RJ. (2013) SLC17: a functionally diverse family of organic anion transporters. Mol Aspects Med 34: 350359. [PMID:23506876]

Shobeiri N, Adams MA, Holden RM. (2013) Phosphate: an old bone molecule but new cardiovascular risk factor. Br J Clin Pharmacol [Epub ahead of print]. [PMID:23506202]

SLC18 family of vesicular amine transporters

Overview

The vesicular amine transporters (VATs) are putative 12 TM domain proteins that function to transport singly positively charged amine neurotransmitters and hormones from the cytoplasm and concentrate them within secretory vesicles. They function as amine/proton antiporters driven by secondary active transport utilizing the proton gradient established by a multi-subunit vacuolar ATPase that acidifies secretory vesicles (reviewed by [283]). The vesicular acetylcholine transporter (VAChT; [287]) localizes to cholinergic neurons, but non-neuronal expression has also been claimed [290]. Vesicular monoamine transporter 1 (VMAT1, [285]) is mainly expressed in peripheral neuroendocrine cells, but most likely not in the CNS, whereas VMAT2 [286] distributes between both central and peripheral sympathetic monoaminergic neurones [284].

NomenclatureVesicular monoamine transporter 1 Vesicular monoamine transporter 2 Vesicular acetylcholine transporter solute carrier family 18, subfamily B, member 1
Systematic nomenclatureSLC18A1SLC18A2SLC18A3SLC18B1
Common abbreviationVMAT1VMAT2VAChT
HGNC, UniProtSLC18A1, P54219 SLC18A2, Q05940 SLC18A3, Q16572 SLC18B1, Q6NT16
Endogenous substrates5-HT (Ki 1.4x10-6 M) [286], (-)-adrenaline (Ki 5.5x10-6 M) [286], (-)-noradrenaline (Ki 1.37x10-5 M) [286], dopamine (Ki 3.8x10-6 M) [286], histamine (Ki 4.696x10-3 M) [286]5-HT (Ki 9x10-7 M) [286], (-)-adrenaline (Ki 1.9x10-6 M) [286], (-)-noradrenaline (Ki 3.4x10-6 M) [286], dopamine (Ki 1.4x10-6 M) [286], histamine (Ki 1.43x10-4 M) [286]acetylcholine (Ki 7.94x10-4 M) [280, 288], choline (Ki 5x10-4 M) [280, 288]
Substratesβ-phenylethylamine (Ki 3.4x10-5 M) [286], dextroamphetamine (Ki 4.7x10-5 M) [286], MPP+ (Ki 6.9x10-5 M) [286], MDMA (Ki 1.9x10-5 M) [286], fenfluramine (Ki 3.1x10-6 M) [286]β-phenylethylamine (Ki 3.7x10-6 M) [286], dextroamphetamine (Ki 2.1x10-6 M) [286], MPP+ (Ki 8.9x10-6 M) [286], MDMA (Ki 6.9x10-6 M) [286], fenfluramine (Ki 5.1x10-6 M) [286]TPP+ [281], ethidium [281], N-methyl-pyridinium-2-aldoxime [281], N-(4′-pentanonyl)-4-(4″-dimethylamino-styryl)pyridinium [281]
Inhibitors (pIC50)reserpine (pKi 7.45) [286], ketanserin (pKi 5.8) [286], tetrabenazine (pKi 4.7) [286]reserpine (pKi 7.9) [286], tetrabenazine (pKi 7.0) [286], ketanserin (pKi 6.3) [286]aminobenzovesamicol (pKi 10.9) [282], vesamicol (pKi 8.7) [282]
Radioligands (Kd)[11C]DTBZ, [125I]8-azido-3-iodoketanserine, [3H]TBZOH (6.6x10-9 M) [291], [125I]iodovinyl-TBZ (8.2x10-9 M) [289][123I]iodobenzovesamicol, [3H]vesamicol (4.1x10-9 M) [291]
Stoichiometry1 amine (in): 2H+ (out)1 amine (in): 2H+ (out)1 amine (in): 2H+ (out)

Comments

pKi values for endogenous and synthetic substrate inhibitors of human VMAT1 and VMAT2 are for inhibition of [3H]5-HT uptake in transfected and permeabilised CV-1 cells as detailed by [286]. In addition to the monoamines listed in the table, the trace amines tyramine and β-phenylethylamine are probable substrates for VMAT2 [284]. Probes listed in the table are those currently employed; additional agents have been synthesized (e.g. [292]).

Further reading

Chaudhry FA, Edwards RH, Fonnum F. (2008) Vesicular neurotransmitter transporters as targets for endogenous and exogenous toxic substances. Annu Rev Pharmacol Toxicol 48: 277301. [PMID:17883368]

Eiden LE, Weihe E. (2011) VMAT2: a dynamic regulator of brain monoaminergic neuronal function interacting with drugs of abuse. Ann N Y Acad Sci 1216: 8698. [PMID:21272013]

Giboureau N, Som IM, Boucher-Arnold A, Guilloteau D, Kassiou M. (2010) PET radioligands for the vesicular acetylcholine transporter (VAChT). Curr Top Med Chem 10: 15691583. [PMID:20583990]

Khare P, White AR, Mulakaluri A, Parsons SM. (2010) Equilibrium binding and transport by vesicular acetylcholine transporter. Methods Mol Biol 637: 181219. [PMID:20419436]

Lawal HO, Krantz DE. (2013) SLC18: Vesicular neurotransmitter transporters for monoamines and acetylcholine. Mol Aspects Med 34: 360372. [PMID:23506877]

Prado VF, Roy A, Kolisnyk B, Gros R, Prado MA. (2013) Regulation of cholinergic activity by the vesicular acetylcholine transporter. Biochem J 450: 265274. [PMID:23410039]

Ramamoorthy S, Shippenberg TS, Jayanthi LD. (2011) Regulation of monoamine transporters: Role of transporter phosphorylation. Pharmacol Ther 129: 220238. [PMID:20951731]

Wimalasena K. (2011) Vesicular monoamine transporters: structure-function, pharmacology, and medicinal chemistry. Med Res Rev 31: 483519. [PMID:20135628]

SLC19 family of vitamin transporters

Overview

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

NomenclatureReduced folate transporter 1 Thiamine transporter 1 Thiamine transporter 2
Systematic nomenclatureSLC19A1SLC19A2SLC19A3
Common abbreviationFOLTThTr1ThTr2
HGNC, UniProtSLC19A1, P41440 SLC19A2, O60779 SLC19A3, Q9BZV2
Endogenous substratesthiamine monophosphate [298], tetrahydrofolic acid [296], N5-methylfolate [296], Organic phosphates; in particular, adenine nucleotides, Other tetrahydrofolate-cofactorsthiamine thiamine
Substratesfolic acid [296], methotrexate, folinic acid, N5-formyltetrahydrofolate
Radioligands (Kd)[3H]folic acid [293], [3H]methotrexate [293][3H]thiamine [295][3H]thiamine [297]
StoichiometryFolate (in) : organic phosphate (out), precise stoichiometry unknownA facilitative carrier not known to be coupled to an inorganic or organic ion gradientA facilitative carrier not known to be coupled to an inorganic or organic ion gradient

Comments

Loss-of-function mutations in ThTr1 underlie thiamine-responsive megaloblastic anemia syndrome [294].

Further reading

Ganapathy V, Smith SB, Prasad PD. (2004) SLC19: the folate/thiamine transporter family. Pflugers Arch 447: 641646. [PMID:14770311]

Goldman ID, Chattopadhyay S, Zhao R, Moran R. (2010) The antifolates: evolution, new agents in the clinic, and how targeting delivery via specific membrane transporters is driving the development of a next generation of folate analogs. Curr Opin Investig Drugs 11: 14091423. [PMID:21154123]

Matherly LH, Hou Z. (2008) Structure and function of the reduced folate carrier a paradigm of a major facilitator superfamily mammalian nutrient transporter. Vitam Horm 79: 145184. [PMID:18804694]

Yuasa H, Inoue K, Hayashi Y. (2009) Molecular and functional characteristics of proton-coupled folate transporter. J Pharm Sci 98: 16081616. [PMID:18823045]

Zhao R, Diop-Bove N, Visentin M, Goldman ID. (2011) Mechanisms of membrane transport of folates into cells and across epithelia. Annu Rev Nutr 31: 177201. [PMID:21568705]

Zhao R, Goldman ID. (2013) Folate and thiamine transporters mediated by facilitative carriers (SLC19A1-3 and SLC46A1) and folate receptors. Mol Aspects Med 34: 373385. [PMID:23506878]

SLC20 family of sodium-dependent phosphate transporters

Overview

The SLC20 family is looked upon not only as ion transporters, but also as retroviral receptors. As ion transporters, they are sometimes referred to as Type III sodium-phosphate co-transporters, alongside Type I (SLC17 family) and Type II (SLC34 family). PiTs are cell-surface transporters, composed of ten TM domains with extracellular C- and N-termini. PiT1 is a focus for dietary PO34- and vitamin D regulation of parathyroid hormone secretion from the parathyroid gland. PiT2 appears to be involved in intestinal absorption of dietary PO34-.

NomenclatureSodium-dependent phosphate transporter 1 Sodium-dependent phosphate transporter 2
Systematic nomenclatureSLC20A1SLC20A2
Common abbreviationPiT1PiT2
HGNC, UniProtSLC20A1, Q8WUM9 SLC20A2, Q08357
SubstratesAsO43− [299], PO34- [299]PO34- [299]
Stoichiometry>1 Na+ : 1 HPO42- (in)>1 Na+ : 1 HPO42- (in)

Further reading

Biber J, Hernando N, Forster I. (2013) Phosphate transporters and their function. Annu Rev Physiol 75: 535550. [PMID:23398154]

Forster IC, Hernando N, Biber J, Murer H. (2013) Phosphate transporters of the SLC20 and SLC34 families. Mol Aspects Med 34: 386395. [PMID:23506879]

Marks J, Debnam ES, Unwin RJ. (2010) Phosphate homeostasis and the renal-gastrointestinal axis. Am J Physiol Renal Physiol 299: F285-F296. [PMID:20534868]

Miyamoto K, Haito-Sugino S, Kuwahara S, Ohi A, Nomura K, Ito M, Kuwahata M, Kido S, Tatsumi S, Kaneko I et al. (2011) Sodium-dependent phosphate cotransporters: lessons from gene knockout and mutation studies. J Pharm Sci 100: 37193730. [PMID:21567407]

Shobeiri N, Adams MA, Holden RM. (2013) Phosphate: an old bone molecule but new cardiovascular risk factor. Br J Clin Pharmacol [Epub ahead of print]. [PMID:23506202]

SLC22 family of organic cation and anion transporters

Overview

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

Organic cation transporters (OCT)

Overview

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

NomenclatureOrganic cation transporter 1 Organic cation transporter 2 Organic cation transporter 3
Systematic nomenclatureSLC22A1SLC22A2SLC22A3
Common abbreviationOCT1OCT2OCT3
HGNC, UniProtSLC22A1, O15245 SLC22A2, O15244 SLC22A3, O75751
Endogenous substrates5-HT, PGE2, PGF2α, choline dopamine [303], histamine [303], PGE2 [304]5-HT [307], (-)-noradrenaline [307], dopamine [307]
Substratestetraethylammonium, desipramine, MPP+, metformin, acyclovir (+)-tubocurarine [302], tetraethylammonium [302], pancuronium [302], MPP+ [302]quinidine, tetraethylammonium, MPP+
StoichiometryUnknownUnknownUnknown

Comments

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

Organic zwitterions/cation transporters (OCTN)

Overview

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

NomenclatureOrganic cation/carnitine transporter 1 Organic cation/carnitine transporter 2 Carnitine transporter 2
Systematic nomenclatureSLC22A4SLC22A5SLC22A16
Common abbreviationOCTN1OCTN2CT2
HGNC, UniProtSLC22A4, Q9H015 SLC22A5, O76082 SLC22A16, Q86VW1
Endogenous substratesL-carnitine acetyl-L-carnitine, L-carnitine L-carnitine
Substratespyrilamine, tetraethylammonium, verapamil, MPP+ pyrilamine, tetraethylammonium, verapamil, MPP+
StoichiometryUnknownUnknownUnknown

Organic anion transporters (OATs)

Overview

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

NomenclatureOrganic anion transporter 1 Organic anion transporter 2 Organic anion transporter 3 Organic anion transporter 7 Organic anion transporter 5 Organic anion transporter 4
Systematic nomenclatureSLC22A6SLC22A7SLC22A8SLC22A9SLC22A10SLC22A11
Common abbreviationOAT1OAT2OAT3OAT4OAT5
HGNC, UniProtSLC22A6, Q4U2R8 SLC22A7, Q9Y694 SLC22A8, Q8TCC7 SLC22A9, Q8IVM8 SLC22A10, Q63ZE4 SLC22A11, Q9NSA0
Substratesaminohippuric acid, non-steroidal anti-inflammatory drugsPGE2, aminohippuric acid, non-steroidal anti-inflammatory drugscimetidine [305], ochratoxin A [305], estrone-3-sulphate [305], aminohippuric acid [305]ochratoxin A [306]dehydroepiandrosterone sulphate [300], ochratoxin A [300], estrone-3-sulphate [300]
StoichiometryUnknownUnknownUnknownUnknownUnknownUnknown

Urate transporter

NomenclatureUrate anion exchanger 1
Systematic nomenclatureSLC22A12
Common abbreviationURAT1
HGNC, UniProtSLC22A12, Q96S37
Endogenous substratesorotic acid [301], uric acid [301]
StoichiometryUnknown

Orphan or poorly characterized SLC22 family members

Further reading

Burckhardt G. (2012) Drug transport by Organic Anion Transporters (OATs). Pharmacol Ther 136: 106130. [PMID:22841915]

Koepsell H. (2013) The SLC22 family with transporters of organic cations, anions and zwitterions. Mol Aspects Med 34: 413435. [PMID:23506881]

König J, Müller F, Fromm MF. (2013) Transporters and drug-drug interactions: important determinants of drug disposition and effects. Pharmacol Rev 65: 944966. [PMID:23686349]

Motohashi H, Inui K. (2013) Organic cation transporter OCTs (SLC22) and MATEs (SLC47) in the human kidney. AAPS J 15: 581588. [PMID:23435786]

SLC23 family of ascorbic acid transporters

Overview

Predicted to be 12 TM segment proteins, members of this family transport the reduced form of ascorbic acid (while the oxidized form may be handled by members of the SLC2 family (GLUT1/SLC2A1, GLUT3/SLC2A3 and GLUT4/SLC2A4). phloretin is considered a non-selective inhibitor of these transporters, with an affinity in the micromolar range.

NomenclatureSodium-dependent vitamin C transporter 1 Sodium-dependent vitamin C transporter 2 Sodium-dependent vitamin C transporter 3 Sodium-dependent nucleobase transporter
Systematic nomenclatureSLC23A1SLC23A2SLC23A3SLC23A4
Common abbreviationSVCT1SVCT2SVCT3SNBT1
HGNC, UniProtSLC23A1, Q9UHI7 SLC23A2, Q9UGH3 SLC23A3, Q6PIS1 SLC23A4P, –
Endogenous substratesL-ascorbic acid > D-ascorbic acid > dehydroascorbic acid [308]L-ascorbic acid > D-ascorbic acid > dehydroascorbic acid [308]uracil > thymine > guanine, hypoxanthine > xanthine, uridine [309]
Substrates
Inhibitors (pIC50)phloretin [308]5-fluorouracil [309]
Radioligands (Kd)[14C]ascorbic acid [14C]ascorbic acid
Stoichiometry2 Na+: 1 ascorbic acid (in) [308]2 Na+: 1 ascorbic acid (in) [308]1 Na+ : 1 uracil (in) [309]
CommentSLC23A3 does not transport ascorbic acid and remains an orphan transporter.SLC23A4/SNBT1 is found in rodents and non-human primates, but the sequence is truncated in the human genome and named as a pseudogene, SLC23A4P

Further reading

Bürzle M, Suzuki Y, Ackermann D, Miyazaki H, Maeda N, Clémençon B, Burrier R, Hediger MA. (2013) The sodium-dependent ascorbic acid transporter family SLC23. Mol Aspects Med 34: 436454. [PMID:23506882]

May JM. (2011) The SLC23 family of ascorbate transporters: ensuring that you get and keep your daily dose of vitamin C. Br J Pharmacol 164: 17931801. [PMID:21418192]

Rivas CI, Zúñiga FA, Salas-Burgos A, Mardones L, Ormazabal V, Vera JC. (2008) Vitamin C transporters. J Physiol Biochem 64: 357375. [PMID:19391462]

Savini I, Rossi A, Pierro C, Avigliano L, Catani MV. (2008) SVCT1 and SVCT2: key proteins for vitamin C uptake. Amino Acids 34: 347355. [PMID:17541511]

SLC24 family of sodium/potassium/calcium exchangers

Overview

The sodium/potassium/calcium exchange family of transporters utilize the extracellular sodium gradient to drive calcium and potassium co-transport out of the cell. As is the case for NCX transporters (SLC8A family), NKCX transporters are thought to be bidirectional, with the possibility of calcium influx following depolarization of the plasma membrane. Topological modeling suggests the presence of 10 TM domains, with a large intracellular loop between the fifth and sixth TM regions.

NomenclatureSodium/potassium/calcium exchanger 1 Sodium/potassium/calcium exchanger 2 Sodium/potassium/calcium exchanger 3 Sodium/potassium/calcium exchanger 4 Sodium/potassium/calcium exchanger 5 Sodium/potassium/calcium exchanger 6
Systematic nomenclatureSLC24A1SLC24A2SLC24A3SLC24A4SLC24A5SLC24A6
Common abbreviationNKCX1NKCX2NKCX3NKCX4NKCX5NKCX6
HGNC, UniProtSLC24A1, O60721 SLC24A2, Q9UI40 SLC24A3, Q9HC58 SLC24A4, Q8NFF2 SLC24A5, Q71RS6 SLC8B1, Q6J4K2
Stoichiometry4Na+:(1Ca2+ + 1K+)

Comments

NKCX6 exhibits sufficient structural diversity for its function as a NKCX to be questioned [310].

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: 6269. [PMID:18690016]

Schnetkamp PP. (2013) The SLC24 gene family of Na+/Ca2+-K+ exchangers: from sight and smell to memory consolidation and skin pigmentation. Mol Aspects Med 34: 455464. [PMID:23506883]

SLC25 family of mitochondrial transporters

Overview

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

Mitochondrial di- and tri-carboxylic acid transporter subfamily

Overview

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

NomenclatureMitochondrial citrate transporter Mitochondrial dicarboxylate transporter Mitochondrial oxoglutarate carrier Mitochondrial oxodicarboxylate carrier
Systematic nomenclatureSLC25A1SLC25A10SLC25A11SLC25A21SLC25A34 SLC25A35
Common abbreviationCICDICOGCODC
HGNC, UniProtSLC25A1, P53007 SLC25A10, Q9UBX3 SLC25A11, Q02978 SLC25A21, Q9BQT8 SLC25A34, Q6PIV7 SLC25A35, Q3KQZ1
Substratescitric acid, malic acid, PEP malic acid, succinic acid, PO34-, S2O32-, SO42- malic acid, α-ketoglutaric acid α-ketoglutaric acid, α-oxoadipic acid
Inhibitors (pIC50)1,2,3-benzenetricarboxylic acid
StoichiometryMalate2- (in) : H-citrate2- (out)PO34- (in) : malate2- (out)Malate2- (in) : oxoglutarate2- (out)Oxoadipate (in) : oxoglutarate (out)

Mitochondrial amino acid transporter subfamily

Overview

Mitochondrial amino acid transporters can be subdivided on the basis of their substrates. Mitochondrial ornithine transporters play a role in the urea cycle by exchanging cytosolic ornithine (L-ornithine and D-ornithine) for mitochondrial citrulline (L-citrulline and D-citrulline) in equimolar amounts. Further members of the family include transporters of S-adenosylmethionine and carnitine.

NomenclatureMitochondrial glutamate carrier 1 Mitochondrial glutamate carrier 2 AGC1 AGC2
Systematic nomenclatureSLC25A22SLC25A18SLC25A12SLC25A13
Common abbreviationGC1GC2AGC1AGC2
HGNC, UniProtSLC25A22, Q9H936 SLC25A18, Q9H1K4 SLC25A12, O75746 SLC25A13, Q9UJS0
SubstratesL-glutamic acid L-glutamic acid L-glutamic acid, L-aspartic acid, 2-amino-3-sulfinopropanoic acid L-glutamic acid, L-aspartic acid, 2-amino-3-sulfinopropanoic acid
StoichiometryGlutamate : H+ (bidirectional)Glutamate : H+ (bidirectional)Aspartate : glutamate H+ (bidirectional)Aspartate : glutamate H+ (bidirectional)
NomenclatureMitochondrial ornithine transporter 1 Mitochondrial ornithine transporter 2 Carnitine/acylcarnitine carrier
Systematic nomenclatureSLC25A15SLC25A2SLC25A20
Common abbreviationORC1ORC2CAC
HGNC, UniProtSLC25A15, Q9Y619 SLC25A2, Q9BXI2 SLC25A20, O43772
SubstratesL-arginine [311], L-citrulline [311], L-lysine [311], L-ornithine [311]L-arginine [311], L-citrulline [311], L-lysine [311], L-ornithine [311], L-histidine [311], D-histidine [311], D-arginine [311], D-lysine [311], D-ornithine [311], D-citrulline [311]
Stoichiometry1 Ornithine (in) :1 citrulline : 1 H+ (out)1 Ornithine (in) :1 citrulline : 1 H+ (out)
CommentExchanges cytosolic acylcarnitine for mitochondrial carnitine
Nomenclaturesolute carrier family 25, member 47 solute carrier family 25, member 48 ORNT3 CGI-69 MCFP
Systematic nomenclatureSLC25A47SLC25A48SLC25A29SLC25A38 SLC25A39SLC25A40SLC25A44 SLC25A45
Common abbreviationORNT3
HGNC, UniProtSLC25A47, Q6Q0C1 SLC25A48, Q6ZT89 SLC25A29, Q8N8R3 SLC25A38, Q96DW6 SLC25A39, Q9BZJ4 SLC25A40, Q8TBP6 SLC25A44, Q96H78 SLC25A45, Q8N413

Comments

Both ornithine transporters are inhibited by the polyamine spermine [312]. Loss-of-function mutations in these genes are associated with hyperornithinemia-hyperammonemia-homocitrullinuria.

Mitochondrial phosphate transporters

Overview

Mitochondrial phosphate transporters allow the import of inorganic PO34- for ATP production.

NomenclatureMitochondrial phosphate carrier
Systematic nomenclatureSLC25A3
Common abbreviationPHC
HGNC, UniProtSLC25A3, Q00325
StoichiometryPO34- (in) : OH- (out) or PO34- : H+ (in)

Mitochondrial nucleotide transporter subfamily

Overview

Mitochondrial nucleotide transporters, defined by structural similarlities, include the adenine nucleotide translocator family (SLC25A4, SLC25A5, SLC25A6 and SLC25A31), which under conditions of aerobic metabolism, allow coupling between mitochondrial oxidative phosphorylation and cytosolic energy consumption by exchanging cytosolic ADP for mitochondrial ATP. Further members of the mitochondrial nucleotide transporter subfamily convey diverse substrates including CoA, although not all members have had substrates identified.

NomenclatureMitochondrial adenine nucleotide translocator 1 Mitochondrial adenine nucleotide translocator 2 Mitochondrial adenine nucleotide translocator 3 Mitochondrial adenine nucleotide translocator 4
Systematic nomenclatureSLC25A4SLC25A5SLC25A6SLC25A31SLC25A42
Common abbreviationANT1ANT2ANT3ANT4
HGNC, UniProtSLC25A4, P12235 SLC25A5, P05141 SLC25A6, P12236 SLC25A31, Q9H0C2 SLC25A42, Q86VD7
Inhibitors (pIC50)BKA, CATR
StoichiometryADP3- (in) : ATP4- (out)ADP3- (in) : ATP4- (out)ADP3- (in) : ATP4- (out)ADP3- (in) : ATP4- (out)
SubstratesADP
NomenclatureGraves disease carrier Peroxisomal membrane protein Deoxynucleotide carrier 1 S-Adenosylmethionine carrier
Systematic nomenclatureSLC25A16SLC25A17SLC25A19SLC25A26
Common abbreviationGDCPMP34DNCSAMC1
HGNC, UniProtSLC25A16, P16260 SLC25A17, O43808 SLC25A19, Q9HC21 SLC25A26, Q70HW3
SubstratesCoA and congenersADP, ATP, AMP Deoxynucleotide Diphosphates (dNDPs), Deoxynucleotide Triphosphates (dNTPs), Dideoxynucleotide Triphosphates (ddNTPs), Nucleotide Diphosphates (NDPs)S-adenosyl methionine
StoichiometryCoA (in)ATP (in)dNDP (in) : ATP (out)
NomenclatureMitochondrial phosphate carrier 1 Mitochondrial phosphate carrier 2 Mitochondrial phosphate carrier 3 MFT PNC1 SCaMC-3L
Systematic nomenclatureSLC25A24SLC25A23SLC25A25SLC25A32SLC25A33SLC25A36 SLC25A41SLC25A43
Common abbreviationAPC1APC2APC3MFTCPNC2
HGNC, UniProtSLC25A24, Q6NUK1 SLC25A23, Q9BV35 SLC25A25, Q6KCM7 SLC25A32, Q9H2D1 SLC25A33, Q9BSK2 SLC25A36, Q96CQ1 SLC25A41, Q8N5S1 SLC25A43, Q8WUT9

Mitochondrial uncoupling proteins

Overview

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

NomenclatureUncoupling protein 1 Uncoupling protein 2 Uncoupling protein 3
Systematic nomenclatureSLC25A7SLC25A8SLC25A9
Common abbreviationUCP1UCP2UCP3
HGNC, UniProtUCP1, P25874 UCP2, P55851 UCP3, P55916
StoichiometryH+ (in)H+ (in)H+ (in)
NomenclatureUncoupling protein 4 Uncoupling protein 5 KMCP1
Systematic nomenclatureSLC25A27SLC25A14SLC25A30
Common abbreviationUCP4UCP5
HGNC, UniProtSLC25A27, O95847 SLC25A14, O95258 SLC25A30, Q5SVS4
StoichiometryH+ (in)H+ (in)

Miscellaneous SLC25 mitochondrial transporters

Overview

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

Nomenclaturemitochondrial carrier 1 mitochondrial carrier 2 Mitoferrin1 Mitoferrin2
Systematic nomenclatureSLC25A49SLC25A50SLC25A37SLC25A28
HGNC, UniProtMTCH1, Q9NZJ7 MTCH2, Q9Y6C9 SLC25A37, Q9NYZ2 SLC25A28, Q96A46

Further reading

Cioffi F, Senese R, de Lange P, Goglia F, Lanni A, Lombardi A. (2009) Uncoupling proteins: a complex journey to function discovery. Biofactors 35: 417428. [PMID:19626697]

Clémençon B, Babot M, Trézéguet V. (2013) The mitochondrial ADP/ATP carrier (SLC25 family): pathological implications of its dysfunction. Mol Aspects Med 34: 485493. [PMID:23506884]

Gnoni GV, Priore P, Geelen MJ, Siculella L. (2009) The mitochondrial citrate carrier: metabolic role and regulation of its activity and expression. IUBMB Life 61: 987994. [PMID:19787704]

Gutiérrez-Aguilar M, Baines CP. (2013) Physiological and pathological roles of mitochondrial SLC25 carriers. Biochem J 454: 371386. [PMID:23988125]

Palmieri F. (2004) The mitochondrial transporter family (SLC25): physiological and pathological implications. Pflugers Arch 447: 689709. [PMID:14598172]

Palmieri F. (2013) The mitochondrial transporter family SLC25: identification, properties and physiopathology. Mol Aspects Med 34: 465484. [PMID:23266187]

SLC26 family of anion exchangers

Overview

Along with the SLC4 family, the SLC26 family acts to allow movement of monovalent and divalent anions across cell membranes. The predicted topology is of 10–14 TM domains with intracellular C- and N-termini, probably existing as dimers. Within the family, subgroups may be identified on the basis of functional differences, which appear to function as anion exchangers and anion channels (SLC26A7 and SLC26A9).

Selective sulphate transporters

NomenclatureSat-1 DTDST
Systematic nomenclatureSLC26A1SLC26A2
HGNC, UniProtSLC26A1, Q9H2B4 SLC26A2, P50443
SubstratesSO42-, oxalate SO42-
StoichiometrySO42- (in) : anion (out)1 SO42- (in) : 2 Cl- (out)

Chloride/bicarbonate exchangers

NomenclatureDRA Pendrin PAT-1
Systematic nomenclatureSLC26A3SLC26A4SLC26A6
HGNC, UniProtSLC26A3, P40879 SLC26A4, O43511 SLC26A6, Q9BXS9
SubstratesCl- Cl-, HCO3-, formate, I-, OH-Cl-, HCO3-, SO42-, oxalate, formate, I-, OH-
Stoichiometry2 Cl- (in) : 1 HCO3- (out) or 2 Cl- (in) : 1 OH- (out)Unknown1 SO42- (in) : 2 HCO3- (out) or 1 Cl- (in) : 2 HCO3- (out)

Anion channels

Systematic nomenclatureSLC26A7 SLC26A9
HGNC, UniProtSLC26A7, Q8TE54 SLC26A9, Q7LBE3
SubstratesNO3- >> Cl- = Br- = I- > SO42- = L-glutamic acid I- > Br- > NO3- > Cl- > L-glutamic acid
Functional characteristicsVoltage- and time-independent current, linear I-V relationship [315]Voltage- and time-independent current, linear I-V relationship [314]
CommentSLC26A9 has been suggested to operate in two additional modes as a Cl--HCO3- exchanger and as a Na+-anion cotransporter [313]

Other SLC26 anion exchangers

NomenclaturePrestin Tat1 KBAT
Systematic nomenclatureSLC26A5SLC26A8SLC26A10 SLC26A11
Common abbreviationKBAT
HGNC, UniProtSLC26A5, P58743 SLC26A8, Q96RN1 SLC26A10, Q8NG04 SLC26A11, Q86WA9
SubstratesCl-, HCO3- Cl-, SO42-, oxalate HSO4-
StoichiometryUnknownUnknownUnknownUnknown
CommentPrestin has been suggested to function as a molecular motor, rather than a transporterSLC26A10 is a possible pseudogene

Further reading

Alper SL, Sharma AK. (2013) The SLC26 gene family of anion transporters and channels. Mol Aspects Med 34: 494515. [PMID:23506885]

Dorwart MR, Shcheynikov N, Yang D, Muallem S. (2008) The solute carrier 26 family of proteins in epithelial ion transport. Physiology (Bethesda) 23: 104114. [PMID:18400693]

Kato A, Romero MF. (2011) Regulation of electroneutral NaCl absorption by the small intestine. Annu Rev Physiol 73: 261281. [PMID:21054167]

Mount DB, Romero MF. (2004) The SLC26 gene family of multifunctional anion exchangers. Pflugers Arch 447: 710721. [PMID:12759755]

Nofziger C, Dossena S, Suzuki S, Izuhara K, Paulmichl M. (2011) Pendrin function in airway epithelia. Cell Physiol Biochem 28: 571578. [PMID:22116372]

Ohana E, Yang D, Shcheynikov N, Muallem S. (2009) Diverse transport modes by the solute carrier 26 family of anion transporters. J Physiol (Lond) 587 (Pt 10): 21792185. [PMID:19015189]

Soleimani M. (2013) SLC26 Cl(-)/HCO3(-) exchangers in the kidney: roles in health and disease. Kidney Int [Epub ahead of print]. [PMID:23636174]

SLC27 family of fatty acid transporters

Overview

Fatty acid transporter proteins (FATPs) are a family (SLC27) of six transporters (FATP1-6). They have at least one, and possibly six [319, 325], transmembrane segments, and are predicted on the basis of structural similarities to form dimers. SLC27 members have several structural domains: integral membrane associated domain, peripheral membrane associated domain, FATP signature, intracellular AMP binding motif, dimerization domain, lipocalin motif, and an ER localization domain (identified in FATP4 only) [317, 322, 323]. These transporters are unusual in that they appear to express intrinsic very long-chain acyl-CoA synthetase (EC 6.2.1.- , EC 6.2.1.7) enzyme activity. Within the cell, these transporters may associate with plasma and peroxisomal membranes. FATP1-4 and -6 transport long- and very long-chain fatty acids, while FATP5 transports long-chain fatty acids as well as bile acids [321, 325].

Comments

Although the stoichiometry of fatty acid transport is unclear, it has been proposed to be facilitated by the coupling of fatty acid transport to conjugation with coenzyme A to form fatty acyl CoA esters. Small molecule inhibitors of FATP2 [320, 324] and FATP4 [316, 327], as well as bile acid inhibitors of FATP5 [327], have been described; analysis of the mechanism of action of some of these inhibitors suggests that transport may be selectively inhibited without altering enzymatic activity of the FATP.

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

FATP2 has two variants: Variant 1 encodes the full-length protein, while Variant 2 encodes a shorter isoform missing an internal protein segment. FATP6 also has two variants: Variant 2 encodes the same protein as Variant 1 but has an additional segment in the 5' UTR.

Further reading

Anderson CM, Stahl A. (2013) SLC27 fatty acid transport proteins. Mol Aspects Med 34: 516528. [PMID:23506886]

Schwenk RW, Holloway GP, Luiken JJ, Bonen A, Glatz JF. (2010) Fatty acid transport across the cell membrane: regulation by fatty acid transporters. Prostaglandins Leukot Essent Fatty Acids 82: 149154. [PMID:20206486]

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

Overview

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

NomenclatureCNT1 CNT2 CNT3
Systematic nomenclatureSLC28A1SLC28A2SLC28A3
Common abbreviationCNT1CNT2CNT3
HGNC, UniProtSLC28A1, O00337 SLC28A2, O43868 SLC28A3, Q9HAS3
Endogenous substratesadenosine, uridine, thymidine, cytidine adenosine, inosine, guanosine, thymidine adenosine, inosine, uridine, guanosine, thymidine, cytidine
Substratesgemcitabine, zidovudine, zalcitabine formycin B, cladribine, fludarabine, vidarabine, didanosine 5-fluorouridine, zebularine, formycin B, gemcitabine, cladribine, floxuridine, zidovudine, zalcitabine, didanosine
Stoichiometry1 Na+ : 1 nucleoside (in)1 Na+ : 1 nucleoside (in)2 Na+ : 1 nucleoside (in)

Comments

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

SLC29 family

Overview

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 [328]. ENT1-3 are described as broad-spectrum nucleoside transporters.

NomenclatureEquilibrative nucleoside transporter 1 Equilibrative nucleoside transporter 2 Equilibrative nucleoside transporter 3 Plasma membrane monoamine transporter
Systematic nomenclatureSLC29A1SLC29A2SLC29A3SLC29A4
Common abbreviationENT1ENT2ENT3PMAT
HGNC, UniProtSLC29A1, Q99808 SLC29A2, Q14542 SLC29A3, Q9BZD2 SLC29A4, Q7RTT9
Endogenous substratesadenosine [335], inosine [335], hypoxanthine [335], uridine [335], guanosine [335], thymine [335], thymidine [335], cytidine [335], adenine [335]adenosine, inosine, hypoxanthine, uridine, guanosine, thymidine adenosine [328], inosine [328], uridine [328], guanosine [328], thymidine [328], adenine [328]5-HT [329], dopamine [329], histamine [329], tyramine [329]
Substrates2-chloroadenosine, formycin B, tubercidin, gemcitabine, cladribine, floxuridine, pentostatin, vidarabine, cytarabine, zalcitabine, didanosine 2-chloroadenosine, formycin B, tubercidin, gemcitabine, cladribine, vidarabine, zidovudine, cytarabine cordycepin [328], zebularine [328], tubercidin [328], cladribine [328], floxuridine [328], fludarabine [328], zidovudine [328], zalcitabine [328], didanosine [328]tetraethylammonium [329], MPP+ [329]
Inhibitors (pIC50)NBTI (pKi 9.7), draflazine (pKi 9.5), KF24345 (pKi 9.4) [330], NBTGR (pKi 9.3), dilazep (pKi 9.0), dipyridamole (pKi 8.5)cimetidine [329], quinidine [329], quinine [329], rhodamine123 [329], verapamil [329]
Radioligands (Kd)[3H]NBTI (5x10-10 M)
StoichiometryEquilibrativeEquilibrativeEquilibrativeEquilibrative
CommentENT1 has 100-1000-fold lower affinity for nucleobases as compared with nucleosides [335]., The affinities of draflazine, dilazep, KF24345 and dipyridamole at ENT1 transporters are species dependent, exhibiting lower affinity at rat transporters than at human transporters [330, 333]., The loss of ENT1 activity in ENT1-null mice has been associated with a hypermineralization disorder similar to human diffuse idiopathic skeletal hyperostosis [334]Defects in SLC29A3 have been implicated in Histiocytosis-lymphadenopathy plus syndrome (OMIM:602782) and lysosomal storage diseases [331, 332]

Further reading

Baldwin SA, McConkey GA, Cass CE, Young JD. (2007) Nucleoside transport as a potential target for chemotherapy in malaria. Curr Pharm Des 13: 569580. [PMID:17346175]

Cano-Soldado P, Pastor-Anglada M. (2012) Transporters that translocate nucleosides and structural similar drugs: structural requirements for substrate recognition. Med Res Rev 32: 428457. [PMID:21287570]

King AE, Ackley MA, Cass CE, Young JD, Baldwin SA. (2006) Nucleoside transporters: from scavengers to novel therapeutic targets. Trends Pharmacol Sci 27: 416425. [PMID:16820221]

Pastor-Anglada M, Cano-Soldado P, Errasti-Murugarren E, Casado FJ. (2008) SLC28 genes and concentrative nucleoside transporter (CNT) proteins. Xenobiotica 38: 972994. [PMID:18668436]

Young JD, Yao SY, Baldwin JM, Cass CE, Baldwin SA. (2013) The human concentrative and equilibrative nucleoside transporter families, SLC28 and SLC29. Mol Aspects Med 34: 529547. [PMID:23506887]

SLC30 zinc transporter family

Overview

Along with the SLC39 family, SLC30 transporters regulate the movement of zinc ions around the cell. In particular, these transporters remove zinc ions from the cytosol, allowing accumulation into intracellular compartments or efflux through the plasma membrane. ZnT1 is thought to be placed on the plasma membrane extruding zinc, while ZnT3 is associated with synaptic vesicles and ZnT4 and ZnT5 are linked with secretory granules. Membrane topology predictions suggest a multimeric assembly, potentially heteromultimeric [337], with subunits having six TM domains, and both termini being cytoplasmic. Dityrosine covalent linking has been suggested as a mechanism for dimerisation, particularly for ZnT3 [336]. The mechanism for zinc transport is unknown.

NomenclatureSystematic nomenclatureCommon abbreviationHGNC, UniProt
Zinc transporter 1 SLC30A1ZnT1SLC30A1, Q9Y6M5
Zinc transporter 2 SLC30A2ZnT2SLC30A2, Q9BRI3
Zinc transporter 3 SLC30A3ZnT3SLC30A3, Q99726
Zinc transporter 4 SLC30A4ZnT4SLC30A4, O14863
Zinc transporter 5 SLC30A5ZnT5SLC30A5, Q8TAD4
Zinc transporter 6 SLC30A6ZnT6SLC30A6, Q6NXT4
Zinc transporter 7 SLC30A7ZnT7SLC30A7, Q8NEW0
Zinc transporter 8 SLC30A8ZnT8SLC30A8, Q8IWU4
Zinc transporter 9 SLC30A9ZnT9SLC30A9, Q6PML9
Zinc transporter 10 SLC30A10ZnT10SLC30A10, Q6XR72

Comments

ZnT8/SLC30A8 is described as a type 1 diabetes susceptibility gene.

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

Further reading

Bouron A, Oberwinkler J. (2013) Contribution of calcium-conducting channels to the transport of zinc ions. Pflugers Arch [Epub ahead of print]. [PMID:23719866]

Huang L, Tepaamorndech S. (2013) The SLC30 family of zinc transporters - a review of current understanding of their biological and pathophysiological roles. Mol Aspects Med 34: 548560. [PMID:23506888]

Kawasaki E. (2012) ZnT8 and type 1 diabetes. Endocr J 59: 531537. [PMID:22447136]

Palmiter RD, Huang L. (2004) Efflux and compartmentalization of zinc by members of the SLC30 family of solute carriers. Pflugers Arch 447: 744751. [PMID:12748859]

Rungby J. (2010) Zinc, zinc transporters and diabetes. Diabetologia 53: 15491551. [PMID:20490449]

Wang X, Zhou B. (2010) Dietary zinc absorption: A play of Zips and ZnTs in the gut. IUBMB Life 62: 176182. [PMID:20120011]

SLC31 family of copper transporters

Overview

SLC31 family members, alongside the Cu-ATPases are involved in the regulation of cellular copper levels. The CTR1 transporter is a cell-surface transporter to allow monovalent copper accumulation into cells, while CTR2 appears to be a vacuolar/vesicular transporter [341]. 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 [340].

NomenclatureCopper transporter 1 Copper transporter 2
Systematic nomenclatureSLC31A1SLC31A2
Common abbreviationCTR1CTR2
HGNC, UniProtSLC31A1, O15431 SLC31A2, O15432
Endogenous substratescopper [340]copper
Substratescisplatin [339]cisplatin [338]
StoichiometryUnknownUnknown

Comments

Copper accumulation through CTR1 is sensitive to silver ions, but not divalent cations [340].

Further reading

Howell SB, Safaei R, Larson CA, Sailor MJ. (2010) Copper transporters and the cellular pharmacology of the platinum-containing cancer drugs. Mol Pharmacol 77: 887894. [PMID:20159940]

Kim H, Wu X, Lee J. (2013) SLC31 (CTR) family of copper transporters in health and disease. Mol Aspects Med 34: 561570. [PMID:23506889]

Nose Y, Rees EM, Thiele DJ. (2006) Structure of the Ctr1 copper trans'PORE'ter reveals novel architecture. Trends Biochem Sci 31: 604607. [PMID:16982196]

Petris MJ. (2004) The SLC31 (Ctr) copper transporter family. Pflugers Arch 447: 752755. [PMID:12827356]

Zheng W, Monnot AD. (2012) Regulation of brain iron and copper homeostasis by brain barrier systems: implication in neurodegenerative diseases. Pharmacol Ther 133: 177188. [PMID:22115751]

SLC32 vesicular inhibitory amino acid transporter

Overview

The vesicular inhibitory amino acid transporter, VIAAT (also termed the vesicular GABA transporter VGAT), which is the sole representative of the SLC32 family, transports GABA, or glycine, into synaptic vesicles [343, 344], and is a member of the structurally-defined amino acid-polyamine-organocation/APC clan composed of SLC32, SLC36 and SLC38 transporter families (see [349]). VIAAT was originally suggested to be composed of 10 TM segments with cytoplasmic N- and C-termini [347]. 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 [346]. 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 (ΔμH+) established by a vacuolar H+-ATPase [347]. However, one study, [345], 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 [342, 351]. VIAAT knock out mice die between embryonic day 18.5 and birth [350]. 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 [348, 350].

NomenclatureVesicular inhibitory amino acid transporter
Systematic nomenclatureSLC32A1
Common abbreviationVIAAT
HGNC, UniProtSLC32A1, Q9H598
Endogenous substratesglycine, β-alanine, γ-hydroxybutyric acid, GABA (Km 5x10-3 M) [347]
Inhibitors (pIC50)vigabatrin (2.1) [347]
Stoichiometry1 amino acid (in): 1 H+ (out) [344] or 1 amino acid: 2Cl- (in) [345]

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 Int 48: 643649. [PMID:16546297]

Gasnier B. (2000) The loading of neurotransmitters into synaptic vesicles. Biochimie 82: 327337. [PMID:10865121]

Gasnier B. (2004) The SLC32 transporter, a key protein for the synaptic release of inhibitory amino acids. Pflugers Arch 447: 756759. [PMID:12750892]

Schiöth HB, Roshanbin S, Hägglund MG, Fredriksson R. (2013) Evolutionary origin of amino acid transporter families SLC32, SLC36 and SLC38 and physiological, pathological and therapeutic aspects. Mol Aspects Med 34: 571585. [PMID:23506890]

SLC33 acetylCoA transporter

Overview

Acetylation of proteins is a post-translational modification mediated by specific acetyltransferases, using the donor acetyl CoA. SLC33A1/AT1 is a putative 11 TM transporter present on the endoplasmic reticulum, expressed in all tissues, but particularly abundant in the pancreas [353], which imports cytosolic acetyl CoA into these intracellular organelles.

NomenclatureAcetylCoA transporter
Systematic nomenclatureSLC33A1
Common abbreviationACATN1
HGNC, UniProtSLC33A1, O00400
Endogenous substratesacetyl CoA
Radioligands (Kd)[14C]acetylCoA
StoichiometryUnknown

Comments

In heterologous expression studies, acetyl CoA transport through AT1 was inhibited by coenzyme A, but not acetic acid, ATP or UDP-galactose [352]. A loss-of-function mutation in ACATN1/SLC33A1 has been associated with spastic paraplegia (SPG42, [354]), although this observation could not be replicated in a subsequent study [355].

Further reading

Hirabayashi Y, Kanamori A, Nomura KH, Nomura K. (2004) The acetyl-CoA transporter family SLC33. Pflugers Arch 447: 760762. [PMID:12739170]

Hirabayashi Y, Nomura KH, Nomura K. (2013) The acetyl-CoA transporter family SLC33. Mol Aspects Med 34: 586589. [PMID:23506891]

SLC34 family of sodium phosphate co-transporters

Overview

The SLC34 family are sometimes referred to as Type II sodium-phosphate co-transporters, alongside Type I (SLC17 family) and Type III (SLC20 family) transporters. Topological modelling suggests eight TM domains with C- and N- termini in the cytoplasm, and a re-entrant loop at TM7/8. SLC34 family members are expressed on the apical surfaces of epithelia in the intestine and kidneys to regulate body phosphate levels, principally NaPi-IIa and NaPi-IIb, respectively. NaPi-IIa and NaPi-IIb are electrogenic, while NaPiIIc is electroneutral [356].

NomenclatureSodium phosphate 1 Sodium phosphate 2 Sodium phosphate 3
Systematic nomenclatureSLC34A1SLC34A2SLC34A3
Common abbreviationNaPi-IIaNaPi-IIbNaPi-IIc
HGNC, UniProtSLC34A1, Q06495 SLC34A2, O95436 SLC34A3, Q8N130
Stoichiometry3 Na+ : 1 HPO42- (in) [357]3 Na+ : 1 HPO42- (in) [356]2 Na+ : 1 HPO42- (in) [356]

Comments

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

Further reading

Biber J, Hernando N, Forster I. (2013) Phosphate transporters and their function. Annu Rev Physiol 75: 535550. [PMID:23398154]

Forster IC, Hernando N, Biber J, Murer H. (2013) Phosphate transporters of the SLC20 and SLC34 families. Mol Aspects Med 34: 386395. [PMID:23506879]

Marks J, Debnam ES, Unwin RJ. (2010) Phosphate homeostasis and the renal-gastrointestinal axis. Am J Physiol Renal Physiol 299: F285F296. [PMID:20534868]

Miyamoto K, Haito-Sugino S, Kuwahara S, Ohi A, Nomura K, Ito M, Kuwahata M, Kido S, Tatsumi S, Kaneko I et al. (2011) Sodium-dependent phosphate cotransporters: lessons from gene knockout and mutation studies. J Pharm Sci 100: 37193730. [PMID:21567407]

Murer H, Forster I, Biber J. (2004) The sodium phosphate cotransporter family SLC34. Pflugers Arch 447: 763767. [PMID:12750889]

Shobeiri N, Adams MA, Holden RM. (2013) Phosphate: an old bone molecule but new cardiovascular risk factor. Br J Clin Pharmacol [Epub ahead of print]. [PMID:23506202]

SLC35 family of nucleotide sugar transporters

Overview

Glycoprotein formation in the Golgi and endoplasmic reticulum relies on the accumulation of nucleotide-conjugated sugars via the SLC35 family of transporters. These transporters have a predicted topology of 10 TM domains, with cytoplasmic termini, and function as exchangers, swopping nucleoside monophosphates for the corresponding nucleoside diphosphate conjugated sugar. Five subfamilies of transporters have been identified on the basis of sequence similarity, namely SLC35A1, SLC35A2, SLC35A3, SLC35A4 and SLC35A5; SLC35B1, SLC35B2, SLC35B3 and SLC35B4; SLC35C1 and SLC35C2; SLC35D1, SL35D1, SLC35D2 and SLC35D3, and the subfamily of orphan SLC35 transporters, SLC35E1-4 and SLC35F1-5.

NomenclatureUGTREL1 PAPS transporter 1 PAPS transporter 2 YEA
Systematic nomenclatureSLC35B1SLC35B2SLC35B3SLC35B4
HGNC, UniProtSLC35B1, P78383 SLC35B2, Q8TB61 SLC35B3, Q9H1N7 SLC35B4, Q969S0
SubstratesA3P5PS [364]A3P5PS [363]UDP N-acetyl-glucosamine [358], UDP-xylose [358]
Nomenclaturesolute carrier family 35, member E2B
Systematic nomenclatureSLC35E1 SLC35E2 SLC35E2BSLC35E3 SLC35E4
HGNC, UniProtSLC35E1, Q96K37 SLC35E2, P0CK97 SLC35E2B, P0CK96 SLC35E3, Q7Z769 SLC35E4, Q6ICL7
CommentOrphan transporterOrphan transporterOrphan transporterOrphan transporter
Nomenclaturesolute carrier family 35, member F6
Systematic nomenclatureSLC35F1 SLC35F2 SLC35F3 SLC35F4 SLC35F5 SLC35F6
HGNC, UniProtSLC35F1, Q5T1Q4 SLC35F2, Q8IXU6 SLC35F3, Q8IY50 SLC35F4, A4IF30 SLC35F5, Q8WV83 SLC35F6, Q8N357
CommentOrphan transporterOrphan transporterOrphan transporterOrphan transporterOrphan transporter

Further reading

Ishida N, Kawakita M. (2004) Molecular physiology and pathology of the nucleotide sugar transporter family (SLC35). Pflugers Arch 447: 768775. [PMID:12759756]

Song Z. (2013) Roles of the nucleotide sugar transporters (SLC35 family) in health and disease. Mol Aspects Med 34: 590600. [PMID:23506892]

SLC36 family of proton-coupled amino acid transporters

Overview

The SLC36 family of proton-coupled amino acid transporters (or PAT) is highly expressed in the intestine and kidney, having roles in the disposition of amino acids [383]. PAT1 is found on the gut epithelia luminal surface accumulating dietary amino acids, and additionally in lysosomal membranes where it likely functions as an efflux mechanism for amino acids produced during intralysosomal proteolysis [369, 382]. PAT2 is found at the apical membrane of the kidney proximal tubule [372]. PAT1 and PAT2 are predicted to have 11 TM domains with intracellular N-termini [370, 382].