The Concise Guide to Pharmacology 2013/14: Transporters

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.

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.

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).

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 mol-ecule 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.

Ca 2+ -ATPases (EC 3.6.3.8)
Overview: The sarcoplasmic/endoplasmic reticulum Ca 2+ -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 Ca 2+ -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 Ca 2+ -ATPases (SPCA) allow accumulation of calcium and manganese in the Golgi apparatus.

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].

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].

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

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

SLC7 family
Overview: SLC7 family members may be divided into two major groups: cationic amino acid transporters (CATs) and glycoprotein-associated amino acid transporters (gpaATs).
Cationic amino acid transporters are 14 TM proteins, which mediate pH-and sodium-independent transport of cationic amino acids (system y + ), apparently as an exchange mechanism. These transporters are sensitive to inhibition by N-ethylmaleimide. Substrates L-arginine, L-lysine, L-ornithine, L-histidine L-arginine, L-lysine, L-ornithine, L-histidine L-arginine, L-lysine, L-ornithine --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.

Nomenclature
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 b 0,+ AT appear to mediate sodiumindependent system b 0,+ 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 xe-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.

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 -/HCO3transporters (AE1, AE2 and AE3), the electrogenic sodium-dependent HCO3transporters (NBCe1 and NBCe2) and the electroneutral HCO3transporters (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.

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].

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].  [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 Iwithin thyrocytes. Transport of Iby 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 Irequired 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 Iabsorption in the intestine and Isecretion 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/highcapacity 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 noncolonic 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].  [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) -Stoichiometry 2Na + : 1 I - [119]; 1Na + : 1 ClO4 - [118] 2Na + : 1 biotin (or pantothenic acid) [134] 2Na + : 1 monocarboxylate [114] -Comments: I -, perchlorate, thiocyanate and NO3are 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].

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].

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 concentra-tions 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 trans-mitter 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]). ATB 0+ (SLCA14) is a transporter for numerous dipolar and cati-onic 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]. ATB 0+ 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.

Nomenclature
Glycine transporter 1 Glycine transporter 2 ATB 0,+ Proline transporter [195], β-alanine [144][145] L-proline  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].

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. B 0 AT1 (SLC6A19), SLC6A17, SLC6A18, SLC6A20). Others may function as transporters for neurotransmitters or their precursors (i.e. B 0 AT2, SLC6A17) [153].

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 Ca 2+ -ATPase (PMCA) and sarcoplasmic/endoplasmic reticulum Ca 2+ -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.

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][216][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].

SLC11 family of proton-coupled metal ion transporters
Overview: The family of proton-coupled metal ion transporters are responsible for movements of divalent cations, particularly ferrous and manganese ions, across the cell membrane (SLC11A2/DMT1) and across endosomal (SLC11A2/DMT1) or lysosomal/phagosomal membranes (SLC11A1/NRAMP1), dependent on proton transport. Both proteins appear to have 12 TM regions and cytoplasmic N-and C-termini. NRAMP1 is involved in antimicrobial action in macrophages, although its precise mechanism is undefined. Facilitated diffusion of divalent cations into phagosomes may increase intravesicular free radicals to damage the pathogen. Alternatively, export of divalent cations from the phagosome may deprive the pathogen of essential enzyme cofactors. SLC11A1/DMT1 is more widely expressed and appears to assist in divalent cation assimilation from the diet, as well as in phagocytotic cells. Comments: Loss-of-function mutations in NRAMP1 are associated with increased susceptibility to microbial infection (OMIM: 607948). Loss-of-function mutations in DMT1 are associated with microcytic anemia (OMIM: 206100).

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 cyto-plasmic 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.

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. Endogenous substrates ammonium carbonate [246], urea [246], formamide [246] urea [244] Substrates acrylamide [246], acetamide [246],

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 diand tripeptides [251]. 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

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.

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.

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.

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].

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 multisubunit vacuolar ATPase that acidifies secretory vesicles (reviewed by [283] Comments: Loss-of-function mutations in ThTr1 underlie thiamine-responsive megaloblastic anemia syndrome [294].

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 PO3 4and vitamin D regulation of parathyroid hormone secretion from the parathyroid gland. PiT2 appears to be involved in intestinal absorption of dietary PO3 4-.

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.

Stoichiometry Unknown Unknown Unknown
Comments: corticosterone and quinine are able to inhibit all three organic cation transporters.

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

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. Comment --SLC23A3 does not transport ascorbic acid and remains an orphan transporter.

Nomenclature
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

SLC24 family of sodium/potassium/calcium exchangers
Overview: The sodium/potassium/calcium exchange family of transporters utilize the extracellular sodium gradient to drive calcium and potassium co-transport out of the cell. As is the case for NCX transporters (SLC8A family), NKCX transporters are thought to be bidirectional, with the possibility of calcium influx following depolarization of the plasma membrane. Topological modeling suggests the presence of 10 TM domains, with a large intracellular loop between the fifth and sixth TM regions.

Nomenclature
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.

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.

SLC25A45, Q8N413
Comments: Both ornithine transporters are inhibited by the polyamine spermine [312]. Loss-of-function mutations in these genes are associated with hyperornithinemia-hyperammonemiahomocitrullinuria.

Mitochondrial phosphate transporters
Overview: Mitochondrial phosphate transporters allow the import of inorganic PO3 4for ATP production.

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

Miscellaneous SLC25 mitochondrial transporters
Overview: Many of the transporters identified below have yet to be assigned functions and are currently regarded as orphans.

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).  Comment -SLC26A9 has been suggested to operate in two additional modes as a Cl --HCO3exchanger and as a Na + -anion cotransporter [313]  Prestin has been suggested to function as a molecular motor, rather than a transporter -SLC26A10 is a possible pseudogene -

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.

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.

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.

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

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

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].

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

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-polyamineorganocation/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].

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.

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].

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

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].  Substrates THIP [378], betaine, L-azetidine-

SLC38 family of sodium-dependent neutral amino acid transporters
Overview: The SLC38 family of transporters appears to be responsible for the functionally-defined system A and system N mechanisms of amino acid transport and are mostly expressed in the CNS. Two distinct subfamilies are identifiable within the SLC38 transporters. SNAT1, SNAT2 and SNAT4 appear to resemble system A transporters in accumulating neutral amino acids under the influence of the sodium gradient. SNAT3 and SNAT5 appear to resemble system N transporters in utilizing proton co-transport to accumulate amino acids. The predicted membrane topology is of 11 TM domains with an extracellular C-terminus and intracellular N-terminus [394].

SLC39 family of metal ion transporters
Overview: Along with the SLC30 family, SLC39 family members regulate zinc movement in cells. SLC39 metal ion transporters accumulate zinc into the cytosol. Membrane topology modelling suggests the presence of eight TM regions with both termini extracellular or in the lumen of intracellular organelles. The mechanism for zinc transport for many members is unknown but appears to involve co-transport of bicarbonate ions [396][397].  The bicarbonate transport inhibitor DIDS has been reported to inhibit cation accumulation through ZIP14 [396].

SLC41 family of divalent cation transporters
Overview: By analogy with bacterial orthologues, this family is probably magnesium transporters. The prokaryote orthologue, MgtE, is responsible for uptake of divalent cations, while the heterologous expression studies of mammalian proteins suggest Mg 2+ efflux [406], possibly as a result of co-expression of particular protein partners (see [407]). Topological modelling suggests 10 TM domains with cytoplasmic C-and N-termini.

SLC42 family of Rhesus glycoprotein ammonium transporters
Overview: Rhesus is commonly defined as a 'factor' that determines, in part, blood type, and whether neonates suffer from haemolytic disease of the newborn. These glycoprotein antigens derive from two genes, RHCE (P18577) and RHD (Q02161), expressed on the surface of erythrocytes. On erythrocytes, RhAG associates with these antigens and functions as an ammonium transporter. RhBG and RhBG are non-erythroid related sequences associated with epithelia. Topological modelling suggests the presence of 12TM with cytoplasmic N-and C-termini. The majority of information on these transporters derives from orthologues in yeast, plants and bacteria. More recent evidence points to family members being permeable to carbon dioxide, leading to the term gas channels.

SLC43 family of large neutral amino acid transporters
Overview: LAT3 (SLC43A1) and LAT4 (SLC43A2) are transporters with system L amino acid transporter activity, along with the structurally and functionally distinct transporters LAT1 and LAT2 that are members of the SLC7 family. LAT3 and LAT4 contain 12 putative TM domains with both N and C termini located intracellularly. They transport neutral amino acids in a manner independent of Na + and Cland with two kinetic components [412][413]. LAT3/SLC43A1 is expressed in human tissues at high levels in the pancreas, liver, skeletal muscle and fetal liver [412] whereas LAT4/SLC43A2 is primarily expressed in the placenta, kidney and peripheral blood leukocytes [413]. SLC43A3 is expressed in vascular endothelial cells [414] but remains to be characterised. Operates by facilitative diffusion Operates by facilitative diffusion -Comments: Covalent modification of LAT3 by N-ethylmaleimide inhibits its function [412] and at LAT4 inhibits the low-, but not high-affinity component of transport [413].

SLC44 choline transporter-like family
Overview: Members of the choline transporter-like family are encoded by five genes (CTL1-CTL5) with further diversity occurring through alternative splicing of CTL1, 4 and 5 [423]. CTL family members are putative 10TM domain proteins with extracellular termini that mediate Na + -independent transport of choline with an affinity that is intermediate to that of the high affinity choline transporter CHT1 (SLC5A7) and the low affinity organic-cation transporters [OCT1 (SLC22A1) and OCT2 (SLC22A2)] [420]. CLT1 is expressed almost ubiquitously in human tissues [425] and mediates choline transport across the plasma and mitochondrial membranes [419]. Transport of choline by CTL2, which in rodents is expressed as two isoforms (CTL2P1 and CLTP2; [417]) in lung, colon, inner ear and spleen and to a lesser extent in brain, tongue, liver, and kidney, has only recently been demonstrated [417,422]. CTL3-5 remain to be characterized functionally.  [416]; rat renal tubule epithelial cells [426]; human colon carcinoma cells [418]; human keratinocytes [424] and human neuroblastoma cells [427]. Choline uptake by CLT1 is inhibited by numerous organic cations (e.g. [416,[426][427]). In the guinea-pig, CTL2 is a target for antibody-induced hearing loss [421] and in man, a polymorphism in CTL2 constitutes the human neutrophil alloantigen-3a (HNA-3a; [415]).

SLC45 family of putative sugar transporters
Overview: Members of the SLC45 family remain to be fully characterised. SLC45A1 was initially identified in the rat brain, particularly predominant in the hindbrain, as a proton-associated sugar transport, induced by hypercapnia [430]. The protein is predicted to have 12TM domains, with intracellular termini. The SLC45A2 gene is thought to encode a transporter protein that mediates melanin synthesis. Mutations in SLC45A2 are a cause of oculocutaneous albinism type 4 (e.g. [429]), and polymorphisms in this gene are associated with variations in skin and hair color (e.g. [428]).

SLC46 family of folate transporters
Overview: Based on the proptypical member of this family, PCFT, this family includes proton-driven transporters with 11 TM segments. SLC46A1 has been described to act as an intestinal proton-coupled high-affinity folic acid transporter [432], with lower affinity for heme. folic acid accumulation is independent of Na + or K + ion concentrations, but driven by extracellular protons with an as yet undefined stoichiometry.

SLC49 family of FLVCR-related heme transporters
Overview: FLVCR1 was initially identified as a cell-surface attachment site for feline leukemia virus subgroup C [455], and later identified as a cell surface accumulation which exports heme from the cytosol [452]. A recent study indicates that an isoform of FLVCR1 is located in the mitochondria, the site of the final steps of heme synthesis, and appears to transport heme into the cytosol [448]. FLVCR-mediated heme transport is essential for erythropoiesis. Flvcr1 gene mutations have been identified as the cause of PCARP (posterior column ataxia with retinitis pigmentosa (PCARP) [453].There are three paralogs of FLVCR1 in the human genome.
FLVCR2, most similar to FLVCR1 [450], has been reported to function as a heme importer [449]. In addition, a congenital syndrome of proliferative vasculopathy and hydranencephaly, also known as Fowler's syndrome, is associated with a loss-offunction mutation in FLVCR2 [451].
The functions of the other two members of the SLC49 family, MFSD7 and DIRC2, are unknown, although DIRC2 has been implicated in hereditary renal carcinomas [447].

SLC51 family of steroid-derived molecule transporters
Overview: The SLC51 organic solute transporter family of transporters is a pair of heterodimeric proteins which regulate bile salt movements in the bile duct, small intestine and kidney, and elsewhere, as part of the enterohepatic circulation [458,460]. OSTα/OSTβ is also expressed in steroidogenic cells of the brain and adrenal gland, where it may contribute to steroid movement [461]. Bile acid transport is suggested to be facilitative and independent of sodium, potassium, chloride ions or protons [458,460]

SLC52 family of riboflavin transporters
Overview: riboflavin, also known as vitamin B2, is a precursor of the enzyme cofactors flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD). Riboflavin transporters are predicted to possess 10 or 11 TM segments.

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