THE CONCISE GUIDE TO PHARMACOLOGY 2017/18: Transporters

The Concise Guide to PHARMACOLOGY 2017/18 provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), 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. Although the Concise Guide represents approximately 400 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point‐in‐time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.13883/full. Transporters are one of the eight major pharmacological targets into which the Guide is divided, with the others being: G protein‐coupled receptors, ligand‐gated ion channels, voltage‐gated ion channels, other ion channels, nuclear hormone receptors, catalytic receptors and enzymes. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid‐2017, and supersedes data presented in the 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature Committee of the Union of Basic and Clinical Pharmacology (NC‐IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.

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

ABCA subfamily
Transporters → ATP-binding cassette transporter family → ABCA subfamily Retinal-specific transporter of N-retinylPE; loss-of-function mutations are associated with childhood-onset Stargardt disease, a juvenile onset macular degenerative disease. The earlier onset disease is often associated with the more severe and deleterious ABCA4 variants [189]. ABCA4 facilitates the clearance of all-trans-retinal from photoreceptor disc membranes following photoexcitation. ABCA4 can also transport N-11-cis-retinylidene-phosphatidylethanolamine, the Schiff-base adduct of 11-cis-retinal; loss of function mutation cause a buildup of lipofuscin, atrophy of the central retina, and severe progressive loss in vision [435].
Common abreviation ----Comments ABCA5 is a lysosomal protein whose loss of function compromises integrity of lysosomes and leads to intra-endolysosomal accumulation of cholesterol. It has recently been associated with Congenital Generalized Hypertrichosis Terminalis (CGHT), a hair overgrowth syndrome, in a patient with a mutation in ABCA5 that significantly decreased its expression [126].
A recent genome wide association study identified an ABCA6 variant associated with cholesterol levels [541].
Genome wide association studies identify ABCA7 variants as associated with Alzheimer's Disease [253].
Reported to play a role in skin ceramide formation [636]. A recent study shows that ABCA12 expression also impacts cholesterol efflux from macrophages. ABCA12 is postulated to associate with ABCA1 and LXR beta, and stabilize expression of ABCA1. ABCA12 deficiency causes decreased expression of Abca1, Abcg1 and Nr1h2 [187].

ABCB subfamily
Transporters → ATP-binding cassette transporter family → ABCB subfamily Comments Responsible for the cellular export of many therapeutic drugs. The mouse and rat have two Abcb1 genes (gene names; Abcb1a and Abcb1b) while the human has only the one gene, ABCB1.
Endoplasmic reticulum peptide transporter is a hetero-dimer composed of the two half-transporters, TAP1 (ABCB2) and TAP2 (ABCB3). The transporter shuttles peptides into the endoplasmic reticulum where they are loaded onto major histocompatibility complex class I (MHCI) molecules via the macromoldecular peptide-loading complex and are eventually presented at the cell surface, attributing to TAP an important role in the adaptive immune response [486].
Transports phosphatidylcholine from intracellular to extracellular face of the hepatocyte canalicular membrane [415]. Heterozygous ABCB4 variants contribute to mild cholestatic phenotypes, while homozygous deficiency leads to Progressive Intrahepatic Familial Cholestasis (PFIC) Type 3, and increased risk of cholesterol gallstones [251]. Comments A drug efflux transporter that has been shown to identify cancer stem-like cells in diverse human malignancies, and is also identified as a limbal stem cell that is required for corneal development and repair [324,569].
Putative mitochondrial porphyrin transporter [321]; other subcellular localizations are possible, such as the plasma membrane, as a specific determinant of the Langereis blood group system [247]. Loss of Abcb6 expression in mice leads to decreased expression and activity of CYP450 [86].
Mitochondrial; reportedly essential for haematopoiesis [427]. Deletion studies in mice demonstrate that Abcb7 is essential in mammals and substantiate a role for mitochondria in cytosolic Fe-S cluster assembly [428].
Mitochondrial; suggested to play a role in chemoresistance of melanoma [154]. Cardiac specific deletion of Abcb8 leads to cardiomyopathy and accumulation of mitochondrial iron, and is thus thought to modulate mitochondrial iron export [262].
Mitochondrial location; the first human ABC transporter to have a crystal structure reported [492]. ABCB10 is important in early steps of heme synthesis in the heart and is required for normal red blood cell development [37,514].
Loss-of-function mutations are associated with progressive familial intrahepatic cholestasis type 2 [501]. ATP-dependent transport of bile acids into the confines of the canalicular space by ABCB11 (BSEP) generates an osmotic gradient and thereby, bile flow. Mutations in BSEP that decrease its function or expression cause Progressive Familial Cholestasis Type 2 (PFIC2), which in severe cases, can be fatal in the absence of a liver transplant. Drugs that inhibit BSEP function with IC50 values less than 25 μM [391] or decrease its expression [199] can cause Drug-Induced Liver Injury (DILI) in the form of cholestatic liver injury. Comments Exhibits a broad substrate specificity [31], including LTC 4 (K m 97 nM [340]) and estradiol-17β-glucuronide [505].
Loss-of-function mutations are associated with Dubin-Johnson syndrome, in which plasma levels of conjugated bilirubin are elevated (OMIM: 237500).

Comments
Although reported to facilitate cellular cyclic nucleotide export, this role has been questioned [56] Loss-of-function mutations in ABCC6 are associated with pseudoxanthoma elasticum (OMIM: 264800).
The sulfonyurea drugs (acetohexamide, tolbutamide and glibenclamide) appear to bind sulfonylurea receptors and it has been shown experimentally that tritiated glibenclamide can be used to pull out a 140 kDa protein identified as SUR1 (now known as ABCC8) [443]. SUR2 (ABCC9) has also been identified [264]. However, this is not the full mechanism of action and the functional channel has been characterised as a hetero-octamer formed by four SUR and four K ir 6.2 subunits, with the K ir 6.2 subunits forming the core ion pore and the SUR subunits providing the regulatory properties [382]. Co-expression of K ir 6.2 with SUR1, reconstitutes the ATP-dependent K + conductivity inhibited by the sulfonyureas [264].
Comments: ABCD4 (ENSG00000119688, also known as PMP69, PXMP1-L or P70R) is located at the lysosome and is in involved in the transport of vitamin B12 (cobalamin) from lysosomes into the cytosol [105].

ABCG subfamily
Transporters → ATP-binding cassette transporter family → ABCG subfamily Overview: This family of 'half-transporters' act as homo-or heterodimers; particularly ABCG5 and ABCG8 are thought to be obligate heterodimers. The ABCG5/ABCG heterodimer sterol transporter structure has been determined [616], suggesting an extensive intracellular nucleotide binding domain linked to the transmembrane domains by a fold in the primary sequence. The functional ABCG2 transporter appears to be a homodimer with structural similarities to the ABCG5/ABCG8 heterodimer [617].

Comments
Transports sterols and choline phospholipids [302] Exhibits a broad substrate specificity, including urate and haem, as well as multiple synthetic compounds [302].

Comments on ATP-binding cassette transporter family:
A further group of ABC transporter-like proteins have been identified to lack membrane spanning regions and are not believed to be functional transporters, but appear to have a role in protein translation [98,434]: 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).

F-type and V-type ATPases
Transporters → 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 F 1 or V 1 ) and a membrane complex (F o or V o ). Within each ATPase complex, the two individual sectors appear to function as connected opposing rotary motors, coupling catalysis of ATP synthesis or hydrolysis to proton transport. Both the F-type and V-type ATPases have been assigned enzyme commission number E.C. 3.6.3.14

F-type ATPase
Transporters → F-type and V-type ATPases → 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 F 0 channel domain in the membrane and an F 1 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 F 1 and F 0 motors. The F 1 motor, responsible for ATP turnover, has the subunit composition α3β3γδ .
The F 0 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 F 0 motor proteins have been defined in the human genome.
Information on members of this family may be found in the online database.

V-type ATPase
Transporters → F-type and V-type ATPases → 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 V 1 motor, responsible for ATP turnover, has eight subunits with a composition of A-H. TheV 0 motor, responsible for ion translocation, has six subunits (a-e).
Information on members of this family may be found in the online database.

P-type ATPases
Transporters → 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
Transporters → P-type ATPases → Na + /K + -ATPases Overview: The cell-surface Na + /K + -ATPase is an integral membrane protein which regulates the membrane potential of the cell by maintaining gradients of Na + and K + ions across the plasma membrane, also making a small, direct contribution to membrane potential, particularly in cardiac cells. For every molecule of ATP hydrolysed, the Na + /K + -ATPase extrudes three Na + ions and imports two K + ions. The active transporter is a heteromultimer with incompletely defined stoichiometry, possibly as tetramers of heterodimers, each consisting of one of four large, ten TM domain catalytic α subunits and one of three smaller, single TM domain glycoprotein β-subunits (see table). Additional protein partners known as FXYD proteins (e.g. FXYD2, P54710) appear to associate with and regulate the activity of the pump.
Information on members of this family may be found in the online database.
Comments: Na + /K + -ATPases are inhibited by ouabain and cardiac glycosides, such as digoxin, as well as potentially endogenous cardiotonic steroids [29].

Ca 2+ -ATPases
Transporters → P-type ATPases → Ca 2+ -ATPases 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.
Information on members of this family may be found in the online database.

Comments:
The fungal toxin ochratoxin A has been described to activate SERCA in kidney microsomes [99]. Cyclopiazonic acid [482], thapsigargin [359] and BHQ are widely employed to block SERCA. Thapsigargin has also been described to block the TRPV1 vanilloid receptor [

H + /K + -ATPases
Transporters → P-type ATPases → H + /K + -ATPases Overview: The H + /K + ATPase is a heterodimeric protein, made up of α and β subunits. The α subunit has 10 TM domains and exhibits catalytic and pore functions, while the β subunit has a single TM domain, which appears to be required for intracellular trafficking and stabilising the α subunit. The ATP4A and ATP4B subunits are expressed together, while the ATP12A subunit is suggested to be expressed with the β1 (ATP1B1) subunit of the Na + /K + -ATPase [422].
Information on members of this family may be found in the online database.

Comments:
The gastric H + /K + -ATPase is inhibited by proton pump inhibitors used for treating excessive gastric acid secretion, including dexlansoprazole and a metabolite of esomeprazole.
Information on members of this family may be found in the online database.

Phospholipid-transporting ATPases
Transporters → P-type ATPases → Phospholipid-transporting ATPases Overview: These transporters are thought to translocate the aminophospholipids phosphatidylserine and phosphatidylethanolamine from one side of the phospholipid bilayer to the other to generate asymmetric membranes. They are also proposed to be involved in the generation of vesicles from intracellular and cell-surface membranes.
Information on members of this family may be found in the online database.
Comments: Loss-of-function mutations in ATP8B1 are associated with type I familial intrahepatic cholestasis.

Glutamate transporter subfamily
Transporters → SLC superfamily of solute carriers → SLC1 family of amino acid transporters → Glutamate transporter subfamily Overview: Glutamate transporters present the unusual structural motif of 8TM segments and 2 re-entrant loops [225]. 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 [57,447,589] reviewed by [281]). This structural data is in agreement with the proposed quaternary structure for EAAT2 [203] and several functional studies that propose the monomer is the functional unit [222,315,332,459]. Recent evidence suggests that EAAT3 and EAAT4 may assemble as heterotrimers [402]. 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 [453]. Recent evidence supports altered glutamate transport and novel roles in brain for splice variants of EAAT1 and EAAT2 [202,333]. Three patients with dicarboxylic aminoaciduria (DA) were recently found to have loss-of-function mutations in EAAT3 [29]. 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 pro-moter activation [197,337,456] reviewed by [304]). PPARγ activation (e.g. by rosiglitazone) also leads to enhanced expression of EAAT though promoter activation [452]. In addition, several translational activators of EAAT2 have recently been described [108] along with treatments that increase the surface expression of EAAT2 (e.g. [331,615]), or prevent its down-regulation (e.g. [216]). A thermodynamically uncoupled Clflux, activated by Na + and glutamate [224,291,362] (Na + and aspartate in the case of GltPh [458]), is sufficiently large, in the instances of EAAT4 and EAAT5, to influence neuronal excitability [527,552]. 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 [192].  [153,487,488,545]. K B (or K i ) values derived in uptake assays are generally higher (e.g. [488]). In addition to acting as a poorly transportable inhibitor of EAAT2, (2S,4R)-4-methylglutamate, also known as SYM2081, is a competitive substrate for EAAT1 (K M = 54μM; [257,545]) and additionally is a potent kainate receptor agonist [607] which renders the compound unsuitable for autoradiographic localisation of EAATs [19]. Similarly, at concentrations that inhibit EAAT2, dihydrokainate binds to kainate receptors [504]. WAY-855 and WAY-213613 are both non-substrate inhibitors with a preference for EAAT2 over EAAT3 and EAAT1 [144,145]. NBI-59159 is a non-substrate inhibitor with modest selectivity for EAAT3 over EAAT1 (>10-fold) and EAAT2 (5-fold) [114,142]. Analogously, L-β-threo-benzyl-aspartate (L-β-BA) is a competitive nonsubstrate inhibitor that preferentially blocks EAAT3 versus EAAT1, or EAAT2 [162]. [ 3 H]SYM2081 demonstrates low affinity binding (K D ∼ = 6.0 μM) to EAAT1 and EAAT2 in rat brain homogenates [20] and EAAT1 in murine astrocyte membranes [18], whereas [ 3 H]ETB-TBOA binds with high affinity to all EAATs other than EAAT3 [489]. The novel isoxazole derivative (-)-HIP-A may interact at the same site as TBOA and preferentially inhibit reverse transport of glutamate [107]. Threo-3-methylglutamate induces substrate-like currents at EAAT4, but does not elicit heteroexchange of [ 3 H]-aspartate in synaptosome preparations, inconsistent with the behaviour of a substrate inhibitor [153]. 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 [181,182]. In addition  [544]).

Alanine/serine/cysteine transporter subfamily
Transporters → SLC superfamily of solute carriers → SLC1 family of amino acid transporters → 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 [22,540]. ASCT1 and ASCT2 also exhibit thermodynamically uncoupled chloride channel activity associated with substrate transport [67,598]. Whereas EAATs counter-transport K + (see above) ASCTs do not and their function is independent of the intracellular concentration of K + [598].

SLC2 family of hexose and sugar alcohol transporters
Transporters → SLC superfamily of solute carriers → 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
Transporters → SLC superfamily of solute carriers → SLC2 family of hexose and sugar alcohol transporters → 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 [577].  SLC3 and SLC7 families of heteromeric amino acid transporters (HATs) Transporters → SLC superfamily of solute carriers → 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
Transporters → SLC superfamily of solute carriers → SLC3 and SLC7 families of heteromeric amino acid transporters (HATs) → 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.
Information on members of this family may be found in the online database.

SLC7 family
Transporters → SLC superfamily of solute carriers → SLC3 and SLC7 families of heteromeric amino acid transporters (HATs) → SLC7 family Overview: SLC7 family members may be divided into two major groups: cationic amino acid transporters (CATs) and glycoprotein-associated amino acid transporters (gpaATs). Cationic amino acid transporters are 14 TM proteins, which mediate pH-and sodium-independent transport of cationic amino acids (system y + ), apparently as an exchange mechanism. These transporters are sensitive to inhibition by N-ethylmaleimide.

Nomenclature
High affinity cationic amino acid transporter 1   Comments: CAT4 appears to be non-functional in heterologous expression [571], while SLC7A14 has yet to be characterized. Glycoprotein-associated amino acid transporters are 12 TM proteins, which heterodimerize with members of the SLC3 family to act as cell-surface amino acid exchangers. Heterodimers between 4F2hc and LAT1 or LAT2 generate sodiumindependent 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 sodium-independent 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
Transporters → SLC superfamily of solute carriers → SLC4 family of bicarbonate transporters Overview: Together with the SLC26 family, the SLC4 family of transporters subserve anion exchange, principally of chloride and bicarbonate (HCO -3 ), but also carbonate and hydrogen sulphate (HSO 4 -). 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 -/HCO -3 transporters (AE1, AE2 and AE3), the electrogenic sodium-dependent HCO -3 transporters (NBCe1 and NBCe2) and the electroneutral HCO -3 transporters (NBCn1 and NBCn2). Topographical information derives mainly from study of AE1, abundant in erythrocytes, which sug-gests 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.

SLC5 family of sodium-dependent glucose transporters
Transporters → SLC superfamily of solute carriers → 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 - [175,195,573,574]. Members of the SLC5 and SLC6 families, along with other unrelated Na + cotransporters (i.e. Mhp1 and BetP), share a common structural core that contains an inverted repeat of 5TM α-helical domains [2].

Hexose transporter family
Transporters → SLC superfamily of solute carriers → SLC5 family of sodium-dependent glucose transporters → 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 [573] for an extensive review). SGLT1 is predominantly ex-pressed 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 [132]. and C3, is tolerated (see [573] for a detailed quantification). Although SGLT1 and SGLT2 have been described as high-and lowaffinity sodium glucose co-transporters, respectively, recent work suggests that they have a similar affinity for glucose under phys-iological conditions [258]. Selective blockers of SGLT2, and thus blocking˜50% of renal glucose reabsorption, are in development for the treatment of diabetes (e.g. [84]).

Choline transporter
Transporters → SLC superfamily of solute carriers → SLC5 family of sodium-dependent glucose transporters → 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 [322]. Through recapture of choline generated by the hydrolysis of ACh by acetylcholinesterase, CHT serves to maintain acetylcholine synthesis within the presynaptic terminal [175]. 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 [174]. 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 [528].  [411], or COS-7 cells [17]. 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.

Nomenclature
Sodium iodide symporter, sodium-dependent multivitamin transporter and sodium-coupled monocarboxylate transporters Transporters → SLC superfamily of solute carriers → SLC5 family of sodium-dependent glucose transporters → Sodium iodide symporter, sodium-dependent multivitamin transporter and sodiumcoupled 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 (triiodothyronine) and thyroxine (T 4 ) [49]. 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 B 5 ) uptake in humans [463]. 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 [195]. 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 [195]. SMCT1 is a high-affinity transporter whereas SMCT2 is a lowaffinity 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 B 3 ) in the intestine and kidney [214]. In the small intestine and colon, the physiological substrates for these transporters are nicotinic acid and the shortchain fatty acids acetic acid, propanoic acid, and butyric acid that are produced by bacterial fermentation of dietary fiber [388]. 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 [521]. SMCT1 also functions as a tumour suppressor in the colon as well as in various other non-colonic tissues [196]. 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 [522]; in the colon, the ability of SMCT1 to transport butyric acid and propanoic acid, also inhibitors of histone deacetylases, underlies the tumoursuppressive function of this transporter [195,196,233]. 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 [495].

Sodium myo-inositol cotransporter transporters
Transporters → SLC superfamily of solute carriers → SLC5 family of sodium-dependent glucose transporters → 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 [48]. 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 [16].

GABA transporter subfamily
Transporters → SLC superfamily of solute carriers → SLC6 neurotransmitter transporter family → 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 GABA A receptors in certain neuronal populations [484]. 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 [364]. 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 [89,241]. CT1, which transports creatine, has a ubiquitous expression pattern, often co-localizing with creatine kinase [89].  has at least an order of magnitude selectivity for BGT1 [see [107,480] for reviews]. Compound (R)-4d is a recently described compound that displays 20-fold selectivity for GAT3 over GAT1 [190].
In addition to the inhibitors listed, deramciclane is a moderately potent, though non-selective, inhibitor of all cloned GABA transporters (IC 50 = 26-46 μM; [127]). Diaryloxime and diarylvinyl ether derivatives of nipecotic acid and guvacine that potently inhibit the uptake of [ 3 H]GABA into rat synaptosomes have been described [309]. Several derivatives of exo-THPO (e.g. N-methyl-exo-THPO and N-acetyloxyethyl-exo-THPO) demonstrate selectivity as blockers of astroglial, versus neuronal, up-take of GABA [see [102,479] for reviews]. GAT3 is inhibited by physiologically relevant concentrations of Zn 2+ [106]. 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 [133]. Although inhibitors of creatine transport by CT1 (e.g. β-guanidinopropionic acid, cyclocreatine, guanidinoethane sulfonic acid) are known (e.g. [114]) they insufficiently characterized to be included in the table.

Glycine transporter subfamily
Transporters → SLC superfamily of solute carriers → SLC6 neurotransmitter transporter family → 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 [42,165,211,504] for reviews). GlyT1 transporter isoforms expressed in glia surrounding glutamatergic synapses regulate synaptic glycine concentrations influencing NMDA receptor-mediated neurotransmission [41,191], but also are important, in early neonatal life, for regulating glycine concentrations at inhibitory glycinergic synapses [212]. Homozy-gous mice engineered to totally lack GlyT1 exhibit severe respiratory and motor deficiencies due to hyperactive glycinergic signalling and die within the first postnatal day [212,530]. 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 [588]. 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 [213,457]. Mice in which GlyT2 has been deleted develop a fatal hyperekplexia phenotype during the second postnatal week [213] and mutations in the human gene encoding GlyT2 (SLC6A5) have been identified in patients with hyperekplexia (reviewed by [243]). ATB 0+ (SLC6A14) is a transporter for numerous dipolar and cationic amino acids and thus has a much broader substrate specificity than the glycine transporters alongside which it is grouped on the basis of structural similarity [89]. ATB 0+ is expressed in various peripheral tissues [89]. 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.

Neutral amino acid transporter subfamily
Transporters → SLC superfamily of solute carriers → SLC6 neurotransmitter transporter family → 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) [69].

SLC8 family of sodium/calcium exchangers
Transporters → SLC superfamily of solute carriers → 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 direc-tion 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
Transporters → SLC superfamily of solute carriers → 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 [389,397,405]. Li + and NH 4 + , 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 [557] and osteoclasts [338]; gene disruption results in infertile male mice [557].
Information on members of this family may be found in the online database.  [119,308]. SLC10A6 (SOAT) functions as a sodium-dependent transporter of sulphated solutes including sulfphated steroids and bile acids [205,207]. 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 iden-tity of their endogenous substrates remain unknown [176,207,210,553]. Members of the SLC10 family are predicted to have seven transmembrane domains with an extracellular N-terminus and cytoplasmic C-terminus [35,236].  [373] glycodeoxycholic acid > glycoursodeoxycholic acid, glycochenodeoxycholic acid > taurocholic acid > cholic acid [112] pregnenolone sulphate [205], estrone-3-sulphate, dehydroepiandrosterone sulphate [207], taurolithocholic acid-3-sulphate Stoichiometry 2 Na + : 1 bile acid [35,205] >1  [206] or SLC10A7 [210] failed to exhibit significant transport of taurocholic acid, pregnenolone sulphate, dehydroepiandrosterone sulphate or choline. SLC10A4 has recently been suggested to associate with neuronal vesicles [72]. 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), depen-dent on proton transport. Both proteins appear to have 12 TM regions and cytoplasmic N-and C-termini. NRAMP1 is involved in antimicrobial action in macrophages, although its precise mechanism is undefined. Facilitated diffusion of divalent cations into phagosomes may increase intravesicular free radicals to damage the pathogen. Alternatively, export of divalent cations from the phagosome may deprive the pathogen of essential enzyme cofactors. SLC11A2/DMT1 is more widely expressed and appears to assist in divalent cation assimilation from the diet, as well as in phagocytotic cells. Comments: Loss-of-function mutations in NRAMP1 are associated with increased susceptibility to microbial infection (OMIM: 607948). Loss-of-function mutations in DMT1 are associated with microcytic anemia (OMIM: 206100).

Further reading on SLC11 family of proton-coupled metal ion transporters
Codazzi 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.

Inhibitors -
Comments: DIOA is able to differentiate KCC isoforms from NKCC and NCC transporters, but also inhibits CFTR [275].  Overview: Within the SLC13 family, two groups of transporters may be differentiated on the basis of the substrates transported: NaS1 and NaS2 convey sulphate, while NaC1-3 transport carboxylates. NaS1 and NaS2 transporters are made up of 13 TM domains, with an intracellular N terminus and are electrogenic with physiological roles in the intestine, kidney and placenta. NaC1, NaC2 and NaC3 are made up of 11 TM domains with an intracellular N terminus and are electrogenic, with physiological roles in the kidney and liver.

Nomenclature
Na  (PEPT2) mainly allows renal tubular reuptake of di/tripeptides from ultrafiltration and brain-to-blood efflux of di/tripeptides in the choroid plexus, SLC15A3 (PHT2) and SLC15A4 (PHT1) interact with both di/tripeptides and histidine, e.g. in certain immune cells, and SLC15A5 has unknown physiological function. In addition, the SLC15 family of peptide transporters variably inter-acts with a very large number of peptidomimetics and peptidelike drugs. It is conceivable, based on the currently acknowledged structural and functional differences, to divide the SLC15 family of peptide transporters into two subfamilies. Endogenous substrates dipeptides [147], tripeptides [147] dipeptides, tripeptides L-histidine [467], carnosine [467], histidyl-leucine [467] carnosine [43,584], L-histidine [43,314,367,561,584] Stoichiometry Transport is electrogenic and involves a variable proton-to-substrate stoichiometry for uptake of neutral and mono-or polyvalently charged peptides.
Transport is electrogenic and involves a variable proton-to-substrate stoichiometry for uptake of neutral and mono-or polyvalently charged peptides. Comments: The members of the SLC15 family of peptide transporters are particularly promiscuous in the transport of di/tripeptides, and D-amino acid containing peptides are also transported. While SLC15A3 and SLC15A4 transport histidine, none of them transport tetrapeptides. In addition, many molecules, among which beta-lactam antibiotics, angiotensin-converting enzyme inhibitors and sartans, variably interact with the SLC15 family transporters. Known substrates include cefadroxil, valacyclovir, 5-aminolevulinic acid, L-Dopa prodrugs, gemcitabine prodrugs, floxuridine prodrugs, Maillard reaction products, JBP485, zanamivir and oseltamivir prodrugs, and didanosine prodrugs.
There is evidence to suggest the existence of a fifth member of this transporter family, SLC15A5 (A6NIM6; ENSG00000188991), but to date there is no established biological function or reported pharmacology for this protein [498].

SLC16 family of monocarboxylate transporters
Transporters → SLC superfamily of solute carriers → 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.

SLC17 phosphate and organic anion transporter family
Transporters → SLC superfamily of solute carriers → 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
Transporters → SLC superfamily of solute carriers → SLC17 phosphate and organic anion transporter family → Type I sodium-phosphate co-transporters Overview: Type I sodium-phosphate co-transporters are expressed in the kidney and intestine.

Sialic acid transporter
Transporters → SLC superfamily of solute carriers → SLC17 phosphate and organic anion transporter family → 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 [387], 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 glutamate transporters (VGLUTs)
Transporters → SLC superfamily of solute carriers → SLC17 phosphate and organic anion transporter family → 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 [39].

Vesicular nucleotide transporter
Transporters → SLC superfamily of solute carriers → SLC17 phosphate and organic anion transporter family → 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 [473].

SLC18 family of vesicular amine transporters
Transporters → SLC superfamily of solute carriers → 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 [151]). The vesicular acetylcholine transporter (VAChT; [160]) localizes to cholinergic neurons, but non-neuronal expression has also been claimed [476]. Vesicular monoamine transporter 1 (VMAT1, [158]) is mainly expressed in peripheral neuroendocrine cells, but most likely not in the CNS, whereas VMAT2 [159] distributes between both central and peripheral sympathetic monoaminergic neurones [152]. The vescular polyamine transporter (VPAT) is highly expressed in the lungs and placenta, with moderate expression in brain and testis, and with low expression in heart and skeletal muscle [250]. VPAT mediates vesicular accumulation of polyamines in mast cells [510].

SLC19 family of vitamin transporters
Transporters → SLC superfamily of solute carriers → 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.

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

SLC22 family of organic cation and anion transporters
Transporters → SLC superfamily of solute carriers → 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.

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

Nomenclature
Sodium

Mitochondrial di-and tri-carboxylic acid transporter subfamily
Transporters → SLC superfamily of solute carriers → SLC25 family of mitochondrial transporters → Mitochondrial di-and tri-carboxylic acid transporter subfamily Overview: Mitochondrial di-and tri-carboxylic acid transporters are grouped on the basis of commonality of substrates and include the citrate transporter which facilitates citric acid export from the mitochondria to allow the generation of oxalacetic acid and acetyl CoA through the action of ATP:citrate lyase.

Nomenclature
Mitochondrial

Mitochondrial amino acid transporter subfamily
Transporters → SLC superfamily of solute carriers → SLC25 family of mitochondrial transporters → 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.

Miscellaneous SLC25 mitochondrial transporters
Transporters → SLC superfamily of solute carriers → SLC25 family of mitochondrial transporters → Miscellaneous SLC25 mitochondrial transporters Overview: Many of the transporters identified below have yet to be assigned functions and are currently regarded as orphans.
Information on members of this family may be found in the online database.

SLC26 family of anion exchangers
Transporters → SLC superfamily of solute carriers → 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).

Functional Characteristics
Voltage-and time-independent current, linear I-V relationship [305] Voltage-and time-independent current, linear I-V relationship [139] Comments -SLC26A9 has been suggested to operate in two additional modes as a Cl --HCO -3 exchanger and as a Na + -anion cotransporter [83].   (FATP1-6). They have at least one, and possibly six [343,475], transmembrane segments, and are predicted on the basis of structural similarities to form dimers. SLC27 members have several structural domains: integral mem-brane 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) [166,383,413]. 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 [381,475].

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 [345,471] and FATP4 [50,609], as well as bile acid inhibitors of FATP5 [609], 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.

SLC28 and SLC29 families of nucleoside transporters
Transporters → SLC superfamily of solute carriers → SLC28 and SLC29 families of nucleoside transporters Overview: Nucleoside transporters are divided into two families, the sodium-dependent, concentrative solute carrier family 28 (SLC28) and the equilibrative, solute carrier family 29 (SLC29). The endogenous substrates are typically nucleosides, although some family members can also transport nucleobases and organic cations.

SLC28 family
Transporters → SLC superfamily of solute carriers → SLC28 and SLC29 families of nucleoside transporters → SLC28 family Overview: SLC28 family membersappear to have 13 TM segments with cytoplasmic N-termini and extracellular C-termini, and function as concentrative nucleoside transporters. Comments: A further two Na + -dependent (stoichiometry 1 Na + : 1 nucleoside (in)) nucleoside transporters have been defined on the basis of substrate and inhibitor selectivity: CNT4 (N4/cit, which transports uridine, thymidine and guanosine) and CNT5 (N5/csg, which transports guanosine and adenosine, and may be inhibited by nitrobenzylmercaptopurine ribonucleoside).
Uptake of substrates by PMAT is pH dependent, with greater uptake observed at acidic extracellular pH; adenosine uptake is only observed at a pH of < 7.0 [36,608].

SLC30 zinc transporter family
Transporters → SLC superfamily of solute carriers → 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 [506], with subunits having six TM domains, and both termini being cytoplasmic. Dityrosine cova-lent linking has been suggested as a mechanism for dimerisation, particularly for ZnT3 [469]. The mechanism for zinc transport is unknown.
Information on members of this family may be found in the online database.
Comments: ZnT8/SLC30A8 is described as a type 1 diabetes susceptibility gene.

SLC31 family of copper transporters
Transporters → SLC superfamily of solute carriers → 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 [442]. 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 [334].

SLC32 vesicular inhibitory amino acid transporter
Transporters → SLC superfamily of solute carriers → 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 [200,201], and is a member of the structurally-defined amino acid-polyamineorganocation/APC clan composed of SLC32, SLC36 and SLC38 transporter families (see [477]). VIAAT was originally suggested to be composed of 10 TM segments with cytoplasmic N-and C-termini [372]. 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 [369]. 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 ( pH) and electrical ( ψ) components of the proton electrochemical gradient ( μ H +) established by a vacuolar H + -ATPase [372]. However, one study, [286], pre-sented 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 [169,595]. VI-AAT knock out mice die between embryonic day 18.5 and birth [570]. 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 [466,570].

SLC33 acetylCoA transporter
Transporters → SLC superfamily of solute carriers → 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 [293], 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 [282]. A loss-of-function mutation in ACATN1/SLC33A1 has been associated with spastic paraplegia (SPG42, [349]), although this observation could not be replicated in a subsequent study [478].
[ 3 H] or [ 14 C] labelled substrates as listed above are used as probes. Loss-of-function mutations in PAT2 lead to iminoglycinuria and hyperglycinuria in man [70]. PAT2 can also function as an electroneutral transport system for protons and fatty acids including acetic acid, propanoic acid and butyric acid [180]. Endogenous substrates -L-tryptophan [423], L-proline [423] Stoichiometry Unknown Unknown

Comments
The function of the testes-specific PAT3 remains unknown.
PAT4 is not proton-coupled and functions by facilitated diffusion in an electroneutral, Na + -independent, manner [423]. PAT4 is expressed ubiquitously. High PAT4 expression is associated with reduced relapse-free survival after colorectal cancer surgery [167].

SLC38 family of sodium-dependent neutral amino acid transporters
Transporters → SLC superfamily of solute carriers → 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 [477].

SLC39 family of metal ion transporters
Transporters → SLC superfamily of solute carriers → 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 [209,354].

SLC40 iron transporter
Transporters → SLC superfamily of solute carriers → SLC40 iron transporter Overview: Alongside the SLC11 family of proton-coupled metal transporters, ferroportin allows the accumulation of iron from the diet. Whilst SLC11A2 functions on the apical membrane, ferroportin acts on the basolateral side of the enterocyte, as well as regulating macrophage and placental iron levels. The predicted topology is of 12 TM domains, with intracellular termini [448], with the functional transporter potentially a dimeric arrangement [4,121]. Ferroportin is essential for iron homeostasis [138]. Ferroportin is expressed on the surface of cells that store and transport iron, such as duodenal enterocytes, hepatocytes, adipocytes and reticuloendothelial macrophages. Levels of ferroportin are regulated by its association with (binding to) hepcidin, a 25 amino acid hormone responsive to circulating iron levels (amongst other signals). Hepcidin binding targets ferroportin for internalisation and degradation, lowering the levels of iron export to the blood. Novel therapeutic agents which stabilise ferroportin or protect it from hepcidin-induced degradation are being developed as antianemia agents. Anti-ferroportin monoclonal antibodies are such an agent.

Stoichiometry
Operates by facilitative diffusion Operates by facilitative diffusion Comments: Covalent modification of LAT3 by N-ethylmaleimide inhibits its function [27] and at LAT4 inhibits the low-, but not high-affinity component of transport [53]. 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 [528]. 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 organiccation transporters [OCT1 (SLC22A1) and OCT2 (SLC22A2)] [380]. CLT1 is expressed almost ubiquitously in human tissues [568] and mediates choline transport across the plasma and mitochondrial membranes [379]. Transport of choline by CTL2, which in rodents is expressed as two isoforms (CTL2P1 and CLTP2; [318]) in lung, colon, inner ear and spleen and to a lesser extent in brain, tongue, liver, and kidney, has only recently been demonstrated [318,398]. CTL3-5 remain to be characterized functionally.

Nomenclature
Choline Overview: These proton:organic cation exchangers are predicted to have 13 TM segments [603] and are suggested to be responsible for excretion of many drugs in the liver and kidneys.

Nomenclature
Heme transporter

SLC49 family of FLVCR-related heme transporters
Transporters → SLC superfamily of solute carriers → SLC49 family of FLVCR-related heme transporters Overview: FLVCR1 was initially identified as a cell-surface attachment site for feline leukemia virus subgroup C [509], and later identified as a cell surface accumulation which exports heme from the cytosol [436]. 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 [96]. FLVCR-mediated heme transport is essential for erythro-poiesis. Flvcr1 gene mutations have been identified as the cause of PCARP (posterior column ataxia with retinitis pigmentosa (PCARP) [438].There are three paralogs of FLVCR1 in the human genome. FLVCR2, most similar to FLVCR1 [351], has been reported to function as a heme importer [141]. In addition, a congenital syndrome of proliferative vasculopathy and hydranencephaly, also known as Fowler's syndrome, is associated with a loss-of-function mutation in FLVCR2 [377]. 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 [52].

SLC50 sugar transporter
Transporters → SLC superfamily of solute carriers → SLC50 sugar transporter Overview: A mouse stromal cell cDNA library was used to clone C2. 3 [507], later termed Rag1-activating protein 1, with a sequence homology predictive of a 4TM topology. The plant orthologues, termed SWEETs, appear to be 7 TM proteins, with extracellular N-termini, and the capacity for bidirectional flux of D-glucose [88]. Expression of mouse SWEET in the mammary gland was suggestive of a role in Golgi lactose synthesis [88].

SLC51 family of steroid-derived molecule transporters
Transporters → SLC superfamily of solute carriers → 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 small intestine, bile duct, and liver, as part of the enterohepatic circulation [34,118]. OSTα/OSTβ is also expressed in steroidogenic cells of the brain and adrenal gland, where it may contribute to steroid movement [168].
Bile acid transport is suggested to be facilitative and independent of sodium, potassium, chloride ions or protons [34,118] [34,118,168]. OSTα is suggested to be a seven TM protein, while OSTβ is a single TM 'ancillary' protein, both of which are thought to have intracellular C-termini [347]. Bimolecular fluorescence complementation studies suggest the possibility of OSTα homo-oligomers, as well as OSTα/OSTβ hetero-oligomers [100,347].

Nomenclature
Organic solute transporter subunit α Organic solute transporter subunit β

SLCO family of organic anion transporting polypeptides
Transporters → SLC superfamily of solute carriers → SLCO family of organic anion transporting polypeptides

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