THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: Transporters

The Concise Guide to PHARMACOLOGY 2019/20 is the fourth in this series of biennial publications. The Concise Guide provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (http://www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide represents approximately 400 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point‐in‐time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.14753. Transporters are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein‐coupled receptors, ion channels, nuclear hormone receptors, catalytic receptors and enzymes. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid‐2019, and supersedes data presented in the 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC‐IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.

tein. Membrane topology predictions for other families suggest 3,4,6,7,8,9,10,11,12,13 or 14 TM domains. The SLC transporters include members which function as antiports, where solute movement in one direction is balanced by a solute moving in the reverse direction. Symports allow concentration gradients of one solute to allow co-transport of a second solute across a membrane. A third, relatively small group are equilibrative transporters, which allow solutes to travel across membranes down their concentration gra-dients. 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.

ABCA subfamily
Transporters → ATP-binding cassette transporter family → ABCA subfamily Overview: To date, 12 members of the human ABCA subfamily are identified. They share a high degree of sequence conservation and have been mostly related with lipid trafficking in a wide range of body locations. Mutations in some of these genes have been described to cause severe hereditary diseases related with lipid transport, such as fatal surfactant deficiency or harlequin ichthyosis. In addition, most of them are hypothesized to participate in the subcellular sequestration of drugs, thereby being responsible for the resistance of several carcinoma cell lines against drug treatment [8].

ABCB subfamily
Transporters → ATP-binding cassette transporter family → ABCB subfamily Overview: The ABCB subfamily is composed of four full transporters and two half transporters. This is the only human subfamily to have both half and full types of transporters. ABCB1 was discovered as a protein overexpressed in certain drug resistant tumor cells. It is expressed primarily in the blood brain barrier and liver and is thought to be involved in protecting cells from toxins. Cells that overexpress this protein exhibit multi-drug resistance [142].
Common abbreviation MDR1, PGP1 TAP1 TAP2 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 [568].
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 [377,670].
Putative mitochondrial porphyrin transporter [374]; other subcellular localizations are possible, such as the plasma membrane, as a specific determinant of the Langereis blood group system [285]. Loss of Abcb6 expression in mice leads to decreased expression and activity of CYP450 [103]. Mitochondrial; reportedly essential for haematopoiesis [501]. Deletion studies in mice demonstrate that Abcb7 is essential in mammals and substantiate a role for mitochondria in cytosolic Fe-S cluster assembly [502].
Mitochondrial; suggested to play a role in chemoresistance of melanoma [177]. Cardiac specific deletion of Abcb8 leads to cardiomyopathy and accumulation of mitochondrial iron, and is thus thought to modulate mitochondrial iron export [305].
A homodimeric transport complex that translocates cytosolic peptides into the lumen of lysosome for degradation [145].

Nomenclature ABCB10 ABCB11
Common abbreviation MTABC2 ABC16 HGNC, UniProt ABCB10, Q9NRK6 ABCB11, O95342 Ligands -glycochenodeoxycholic acid (Binding) (pK i 5.2) [89] Comments Mitochondrial location; the first human ABC transporter to have a crystal structure reported [575]. ABCB10 is important in early steps of heme synthesis in the heart and is required for normal red blood cell development [45,606].
Loss-of-function mutations are associated with progressive familial intrahepatic cholestasis type 2 [590]. 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 [450] or decrease its expression [228] can cause Drug-Induced Liver Injury (DILI) in the form of cholestatic liver injury.

ABCC subfamily
Transporters → ATP-binding cassette transporter family → ABCC subfamily Overview: Subfamily ABCC contains thirteen members and nine of these transporters are referred to as Multidrug Resistance Proteins (MRPs). MRP proteins are found throughout nature and mediate many important functions. They are known to be involved in ion transport, toxin secretion, and signal transduction [142].
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 [67]; reported to export prostaglandins in a manner sensitive to NSAIDS [523] Although reported to facilitate cellular cyclic nucleotide export, this role has been questioned [67] Loss-of-function mutations in ABCC6 are associated with pseudoxanthoma elasticum (OMIM: 264800).

Comments
Transports sterols and choline phospholipids [351] Exhibits a broad substrate specificity, including urate and haem, as well as multiple synthetic compounds [351].

SLC superfamily of solute carriers
Transporters → SLC superfamily of solute carriers Overview: The SLC superfamily of solute carriers is the second largest family of membrane proteins after G protein-coupled receptors, but with a great deal fewer therapeutic drugs that exploit them. As with the ABC transporters, however, they play a major role in drug disposition and so can be hugely influential in determining the clinical efficacy of particular drugs. 48 families are identified on the basis of sequence similarities, but many of them overlap in terms of the solutes that they carry. For example, amino acid accumulation is mediated by members of the SLC1, SLC3/7, SLC6, SLC15, SLC16, SLC17, SLC32, SLC36, SLC38 and SLC43. Further members of the SLC superfamily regulate ion fluxes at the plasma membrane, or solute transport into and out of cellular organelles. Within the SLC superfamily, there is an abundance in diversity of structure. Two families (SLC3 and SLC7) only generate functional transporters as heteromeric partners, where one partner is a single TM domain protein. Membrane topology predictions for other families suggest 3, 4 6, 7, 8, 9, 10, 11, 12, 13, or 14 TM domains.
Functionally, members may be divided into those dependent on gradients of ions (particularly sodium, chloride or protons), exchange of solutes or simple equilibrative gating. For many members, the stoichiometry of transport is not yet established. Furthermore, one family of transporters also possess enzymatic activity (SLC27), while many members function as ion channels (e.g. SLC1A7/EAAT5), which increases the complexity of function of the SLC superfamily.

SLC1 family of amino acid transporters
Transporters → SLC superfamily of solute carriers → SLC1 family of amino acid transporters Overview: The SLC1 family of sodium dependent transporters includes the plasma membrane located glutamate transporters and the neutral amino acid transporters ASCT1 and ASCT2 [11,46,338,339,487].

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 [262]. 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 [68,526,696] reviewed by [329]). This structural data is in agreement with the proposed quaternary structure for EAAT2 [232] and several functional studies that propose the monomer is the functional unit [257,366,385,539]. Recent evidence suggests that EAAT3 and EAAT4 may assemble as heterotrimers [467]. 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 [533]. Recent evidence supports altered glutamate transport and novel roles in brain for splice variants of EAAT1 and EAAT2 [231,386]. Three patients with dicarboxylic aminoaciduria (DA) were recently found to have loss-of-function mutations in EAAT3 [35]. 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 [226,390,536] reviewed by [353]). PPARγ activation (e.g. by rosiglitazone) also leads to enhanced expression of EAAT though promoter activation [532]. In addition, several translational activators of EAAT2 have recently been described [125] along with treatments that increase the surface expression of EAAT2 (e.g. [384,726]), or prevent its down-regulation (e.g. [248]). A thermodynamically uncoupled Clflux, activated by Na + and glutamate [259,339,419] (Na + and aspartate in the case of GltPh [538]), is sufficiently large, in the instances of EAAT4 and EAAT5, to influence neuronal excitability [621,648]. 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 [220].  [176,570,571,640]. K B (or K i ) values derived in uptake assays are generally higher (e.g. [571]). 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; [300,640]) and additionally is a potent kainate receptor agonist [715] which renders the compound unsuitable for autoradiographic localisation of EAATs [24]. Similarly, at concentrations that inhibit EAAT2, dihydrokainate binds to kainate receptors [571]. WAY-855 and WAY-213613 are both non-substrate inhibitors with a prefer-ence for EAAT2 over EAAT3 and EAAT1 [166,167]. NBI-59159 is a non-substrate inhibitor with modest selectivity for EAAT3 over EAAT1 (>10-fold) and EAAT2 (5-fold) [126,164]. Analogously, L-β-threo-benzyl-aspartate (L-β-BA) is a competitive nonsubstrate inhibitor that preferentially blocks EAAT3 versus EAAT1, or EAAT2 [186]. [ 3 H]SYM2081 demonstrates low affinity binding (K D ∼ = 6.0 μM) to EAAT1 and EAAT2 in rat brain homogenates [25] and EAAT1 in murine astrocyte membranes [23], whereas [ 3 H]ETB-TBOA binds with high affinity to all EAATs other than EAAT3 [572]. The novel isoxazole derivative (-)-HIP-A may interact at the same site as TBOA and preferentially inhibit reverse transport of glutamate [124]. 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 [176]. 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 [207,208]. In addition to the agents listed in the table, DL-threo-β-hydroxyaspartate and L-trans-2,4-pyrolidine dicarboxylate act as non-selective competitive substrate inhibitors of all EAATs. Zn 2+ and arachidonic acid are putative endogenous modulators of EAATs with actions that differ across transporter subtypes (reviewed by [639]).

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 [27,634]. ASCT1 and ASCT2 also exhibit thermodynamically uncoupled chloride channel activity associated with substrate transport [79,704]. Whereas EAATs counter-transport K + (see above) ASCTs do not and their function is independent of the intracellular concentration of K + [704].

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 [678].

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 Low affinity cationic amino acid transporter 2 Cationic amino acid transporter 3 L-type amino acid transporter 1 L-type amino acid transporter 2 Substrates L-ornithine, L-arginine, L-lysine, L-histidine L-ornithine, L-arginine, L-lysine, L-histidine L-ornithine, L-arginine, L-lysine -- 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. 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.

Anion exchangers
Transporters → SLC superfamily of solute carriers → SLC4 family of bicarbonate transporters → Anion exchangers

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 [674] 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 [153].

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 [375]. Through recapture of choline generated by the hydrolysis of ACh by acetylcholinesterase, CHT serves to maintain acetylcholine synthesis within the presynaptic terminal [200]. 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 [199]. 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 [622]. 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 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 (triiodothyronine) and thyroxine (T 4 ) [59]. 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 [544]. 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 [224]. 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 [224]. 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 [246]. 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 [447]. 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 [615]. SMCT1 also functions as a tumour suppressor in the colon as well as in various other non-colonic tissues [225]. 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 [616]; 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 [224,225,271]. 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 [579].

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 [58]. 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 [21].

SLC6 neurotransmitter transporter family
Transporters → SLC superfamily of solute carriers → SLC6 neurotransmitter transporter family Overview: Members of the solute carrier family 6 (SLC6) of sodium-and (sometimes chloride-) dependent neurotransmitter transporters [80,106,376] 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 [546]. The members of this superfamily share a structural motif of 10 TM segments that has been observed in crystal structures of the NSS bacterial homolog LeuT Aa , a Na + -dependent amino acid transporter from Aquiflex aeolicus [687] and in several other transporter families structurally related to LeuT [209].

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 [566]. 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 [422]. 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 [106,279]. CT1, which transports creatine, has a ubiquitous expression pattern, often co-localizing with creatine kinase [106].

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 [51,189,242,594] for reviews). GlyT1 transporter isoforms expressed in glia surrounding glutamatergic synapses regulate synaptic glycine concentrations influencing NMDA receptor-mediated neurotransmission [50,219], but also are important, in early neonatal life, for regulating glycine concentrations at inhibitory glycinergic synapses [243]. 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 [243,624]. 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 [695]. 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 [244,537]. Mice in which GlyT2 has been deleted develop a fatal hyperekplexia phenotype during the second postnatal week [244] and mutations in the human gene encoding GlyT2 (SLC6A5) have been identified in patients with hyperekplexia (reviewed by [281]). 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 [106]. ATB 0+ is expressed in various peripheral tissues [106]. 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.

Comments:
Sarcosine is a selective transportable inhibitor of GlyT1 and also a weak agonist at the glycine binding site of the NMDA receptor [707], but has no effect on GlyT2. This difference has been attributed to a single glycine residue in TM6 (serine residue in GlyT2) [641]. Inhibition of GLYT1 by the sarcosine derivatives NFPS, NPTS and Org 24598 is non-competitive [424,436]. IC 50 values for Org 24598 reported in the literature vary, most likely due to differences in assay conditions [74,424]. The tricyclic antidepressant amoxapine weakly inhibits GlyT2 (IC 50 92 μM) with approximately 10-fold selectivity over GlyT1 [473]. The endogenous lipids arachidonic acid and anandamide exert opposing effects upon GlyT1a, inhibiting (IC 50 2 μM) and potentiating (EC 50 13 μM) transport currents, respectively [491]. N-arachidonyl-glycine, N-arachidonyl-γ-aminobutyric acid and N-arachidonyl-D-alanine have been described as endogenous non-competitive inhibitors of GlyT2a, but not GlyT1b [170,327,668]. Protons [30] and Zn 2+ [332] act as non-competitive inhibitors of GlyT1b, with IC 50 values of 100 nM and 10 μM respectively, but neither ion affects GlyT2 (reviewed by [639]

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), SLC6A18, SLC6A20). Others may function as transporters for neurotransmitters or their precursors (i.e. B 0 AT2, SLC6A17) [81]. B 0 AT1 has been proposed as a drug target to treat phenylketonuria [47].
L-proline Stoichiometry 1 Na + : 1 amino acid [90] 1N a + : 1 amino acid [78] N a + -and Cl --dependent transport [578] -N a + -dependent, Cl --independent transport [700] 2 Na + : 1 Cl -: 1 imino acid [76] Inhibitors cinromide (pIC 50  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 [448,457,472]. 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 [653] and osteoclasts [391]; gene disruption results in infertile male mice [653].
Information on members of this family may be found in the online database.
Comments: Analogues of the non-selective cation transport inhibitor amiloride appear to inhibit NHE function through competitive inhibition of the extracellular Na + binding site. The more selective amiloride analogues MPA and ethylisopropylamiloride exhibit a rank order of affinity of inhibition of NHE1 > NHE2 > NHE3 [127,625,626].  Chenodeoxycholyl-N -nitrobenzoxadiazol-lysine is a fluorescent bile acid analogue used as a probe [662].

SLC11 family of proton-coupled metal ion transporters
Transporters → SLC superfamily of solute carriers → 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), 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). In mouse studies Slc12a8 has been shown to transport the nicotinamide adenine dinucleotide (NAD+) precursor, nicotinamide mononucleotide (NMN) in to cells, and administration of NMN produces anti-ageing effects in vivo [261].

Further reading on SLC11 family of proton-coupled metal ion transporters
Comments: DIOA is able to differentiate KCC isoforms from NKCC and NCC transporters, but also inhibits CFTR [321].  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.

SLC14 family of facilitative urea transporters
Transporters → SLC superfamily of solute carriers → SLC14 family of facilitative urea transporters Overview: As a product of protein catabolism, urea is moved around the body and through the kidneys for excretion. Although there is experimental evidence for concentrative urea transporters, these have not been defined at the molecular level. The SLC14 family are facilitative transporters, allowing urea movement down its concentration gradient. Multiple splice variants of these transporters have been identified; for UT-A transporters, in particular, there is evidence for cell-specific expression of these variants with functional impact [589]. Topographical modelling suggests that the majority of the variants of SLC14 transporters have 10 TM do-mains, with a glycosylated extracellular loop at TM5/6, and intracellular C-and N-termini. The UT-A1 splice variant, exceptionally, has 20 TM domains, equivalent to a combination of the UT-A2 and UT-A3 splice variants.

Nomenclature
Erythrocyte

SLC15 family of peptide transporters
Transporters → SLC superfamily of solute carriers → SLC15 family of peptide transporters Overview: The Solute Carrier 15 (SLC15) family of peptide transporters, alias H + -coupled oligopeptide cotransporter family, is a group of membrane transporters known for their key role in the cellular uptake of di-and tripeptides (di/tripeptides). Of its members, SLC15A1 (PEPT1) chiefly mediates intestinal absorption of luminal di/tripeptides from overall dietary protein digestion, SLC15A2 (PEPT2) mainly allows renal tubular reuptake of di/tripeptides from ultrafiltration and brain-to-blood efflux of di/tripeptides in the choroid plexus, SLC15A3 (PHT2) and SLC15A4 (PHT1) interact with both di/tripeptides and histidine, e.g. in certain immune cells, and SLC15A5 has unknown physiological function. In addition, the SLC15 family of peptide transporters variably interacts with a very large number of peptidomimetics and peptide-like drugs. It is conceivable, based on the currently acknowledged structural and functional differences, to divide the SLC15 family of peptide transporters into two subfamilies.
Transport is electrogenic and involves a variable proton-to-substrate stoichiometry for uptake of neutral and mono-or polyvalently charged peptides, as well as 5-aminolevulic acid.  [52].

Comments:
The members of the SLC15 family of peptide transporters are particularly promiscuous in the transport of di/tripeptides, and D-amino acid containing peptides are also transported. While SLC15A3 and SLC15A4 transport histidine, none of them transport tetrapeptides. In addition, many molecules, among which beta-lactam antibiotics, angiotensinconverting enzyme inhibitors and sartans, variably interact with the SLC15 family transporters. Known substrates include cefadroxil, valacyclovir, 5-aminolevulinic acid, L-Dopa prodrugs, gemcitabine prodrugs, floxuridine prodrugs, Maillard reaction products, JBP485, zanamivir, oseltamivir prodrugs, doxorubicin prodrugs, polymyxins, and didanosine prodrugs. Frequently used pharmaceutical excipients such as Tween® 20, Tween® 80, Solu-tol® HS 15 and Cremophor EL® strongly inhibit cellular uptake of Gly-Sar by SLC15A1 and/or SLC15A2 [483]. 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 [585].  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 [446], driven by proton gradients. In lysosomes, degradation of glycoproteins generates amino acids and sugar residues, which are metabolized further following export from the lysosome.

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 [48].

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.

Nomenclature
Sodium

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.

Organic cation transporters (OCT)
Transporters → SLC superfamily of solute carriers → SLC22 family of organic cation and anion transporters → Organic cation transporters (OCT) Overview: Organic cation transporters (OCT) are electrogenic, Na + -independent and reversible.

Nomenclature
Organic Comments: Corticosterone and quinine are able to inhibit all three organic cation transporters.

Further reading on Organic cation transporters (OCT)
Koepsell H.

Nomenclature
Organic Comments: Mutations in the SLC22A5 gene lead to primary carnitine deficiency [409].

Organic anion transporters (OATs)
Transporters → SLC superfamily of solute carriers → SLC22 family of organic cation and anion transporters → Organic anion transporters (OATs) Overview: Organic anion transporters (OATs) are non-selective transporters prominent in the kidney, placenta and blood-brain barrier.

Urate transporter
Transporters → SLC superfamily of solute carriers → SLC22 family of organic cation and anion transporters → Urate transporter Overview: URAT1, a member of the OAT (organic anion transporter) family, is an anion-exchanging uptake transporter localized to the apical (brush border) membrane of renal proximal tubular cells.
It is an anion exchanger that specifically reabsorbs uric acid from the proximal tubule in exchange for monovalent anions such as lactate, nicotinoate, acetoacetate, and hydroxybutyrate [181].

SLC23 family of ascorbic acid transporters
Transporters → SLC superfamily of solute carriers → 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. Comments 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

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.  Carnitine/acylcarnitine carrier

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).  Comments -SLC26A9 has been suggested to operate in two additional modes as a Cl --HCO 3 exchanger and as a Na + -anion cotransporter [99].

SLC27 family of fatty acid transporters
Transporters → SLC superfamily of solute carriers → 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 [397,557], 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) [190,441,481]. 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 [439,557].

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 [398,553] and FATP4 [60,718], as well as bile acid inhibitors of FATP5 [718], 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
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.

SLC29 family
Transporters → SLC superfamily of solute carriers → SLC28 and SLC29 families of nucleoside transporters → SLC29 family Overview: SLC29 family members appear to be composed of 11 TM segments with cytoplasmic N-termini and extracellular C-termini. ENT1, ENT2 and ENT4 are cell-surface transporters, while ENT3 is intracellular, possibly lysosomal [38]. ENT1-3 are described as broad-spectrum equilibrative nucleoside transporters, while ENT4 is primarily a polyspecific organic cation transporter at neutral pH [293].
Uptake of substrates by PMAT is pH dependent, with greater uptake observed at acidic extracellular pH [43,717].

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 [596], 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 [551]. 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. Zinc fluxes may be monitored through the use of radioisotopic Zn-65 or the fluorescent dye FluoZin 3.

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 [521]. 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 [387]. Comments: Copper accumulation through CTR1 is sensitive to silver ions, but not divalent cations [387].

Further reading on SLC31 family of copper transporters
Howell SB et al.

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 [229,230], and is a member of the structurally-defined amino acid-polyamineorganocation/APC clan composed of SLC32, SLC36 and SLC38 transporter families (see [559]). VIAAT was originally suggested to be composed of 10 TM segments with cytoplasmic N-and C-termini [429]. 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 [427]. VI-AAT 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 [429]. However, one study, [334], 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 [194,701]. VIAAT knock out mice die between embryonic day 18.5 and birth [671]. In cultures of spinal cord neurones established from earlier embryos, the corelease 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 [547,671].

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 [341], 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 [330]. A loss-of-function mutation in ACATN1/SLC33A1 has been associated with spastic paraplegia (SPG42, [401]), although this observation could not be replicated in a subsequent study [560].

SLC34 family of sodium phosphate co-transporters
Transporters → SLC superfamily of solute carriers → 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 [18].

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

SLC36 family of proton-coupled amino acid transporters
Transporters → SLC superfamily of solute carriers → SLC36 family of proton-coupled amino acid transporters Overview: Members of the SLC36 family of proton-coupled amino acid transporters are involved in membrane transport of amino acids and derivatives. The four transporters show variable tissue expression patterns and are expressed in various cell types at the plasma-membrane and in intracellular organelles. PAT1 is expressed at the luminal surface of the small intestine and absorbs amino acids and derivatives [3]. In lysosomes, PAT1 functions as an efflux mechanism for amino acids produced during intralysosomal proteolysis [5,542]. PAT2 is expressed at the apical membrane of the renal proximal tubule [82] and at the plasma-membrane in brown/beige adipocytes [633]. PAT1 and PAT4 are involved in regulation of the mTORC1 pathway [191]. More comprehensive lists of substrates can be found within the reviews under Further Reading and in the references.

Nomenclature
Proton-coupled sarcosine, L-proline, glycine, L-alanine, trans-4-hydroxy-proline Comments [ 3 H] or [ 14 C] labelled substrates as listed above are used as probes. PAT1 can also function as an electroneutral transport system for protons and fatty acids including acetic acid, propanoic acid and butyric acid [206]. In addition, forskolin, phosphodiesterase inhibitors, amiloride analogues and SLC9A3 (NHE3) selective inhibitors all reduce PAT1 activity indirectly (in intact mammalian intestinal epithelia such as human intestinal Caco-2 cells) by inhibiting the Na + /H + exchanger NHE3 which is required to maintain the H + -electrochemical gradient driving force for H + /amino acid cotransport [14,17,619].
[ 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 [82]. PAT2 can also function as an electroneutral transport system for protons and fatty acids including acetic acid, propanoic acid and butyric acid [206]. Replacement of a Phe residue in transmembrane domain 3 with Cys (that has a smaller side-chain) broadens substrate specificity to include larger substrates (e.g. methionine, leucine) [172]. Endogenous substrates -L-tryptophan [497], L-proline [497] 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 [497]. PAT4 is expressed ubiquitously and is predominantly associated with the Golgi [192].. High PAT4 expression is associated with reduced relapse-free survival after colorectal cancer surgery [192]. The family of sugar-phosphate exchangers pass particular phosphorylated sugars across intracellular membranes, exchanging for inorganic phosphate. Of the family of sugar phosphate transporters, most information is available on SPX4, the glucose-6-phosphate transporter. This is a 10 TM domain protein with cytoplasmic termini and is associated with the endoplasmic reticulum, with tissue-specific splice variation.

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 [240,407]. Comments: Zinc fluxes may be monitored through the use of radioisotopic Zn-65 or the fluorescent dye FluoZin 3. The bicarbonate transport inhibitor DIDS has been reported to inhibit cation accumulation through ZIP14 [240].

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 [527], with the functional transporter potentially a dimeric arrangement [4,140]. Ferroportin is essential for iron homeostasis [160]. 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.

SLC41 family of divalent cation transporters
Transporters → SLC superfamily of solute carriers → 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 [369], possibly as a result of co-expression of particular protein partners (see [543]). Topological modelling suggests 10 TM domains with cytoplasmic C-and N-termini. 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.

Stoichiometry
Operates by facilitative diffusion Operates by facilitative diffusion Comments: Covalent modification of LAT3 by N-ethylmaleimide inhibits its function [33] and at LAT4 inhibits the low-, but not high-affinity component of transport [64].  [622]. 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)] [438]. CLT1 is expressed almost ubiquitously in human tissues [669] and mediates choline transport across the plasma and mitochondrial membranes [437]. Transport of choline by CTL2, which in rodents is expressed as two isoforms (CTL2P1 and CLTP2; [370]) in lung, colon, inner ear and spleen and to a lesser extent in brain, tongue, liver, and kidney, has only recently been demonstrated [370,458]. CTL3-5 remain to be characterized functionally.  [373]; human keratinocytes [630] and human neuroblastoma cells [684]. Choline uptake by CLT1 is inhibited by numerous organic cations (e.g. [308,683,684]). In the guinea-pig, CTL2 is a target for antibody-induced hearing loss [454] and in man, a polymorphism in CTL2 constitutes the human neutrophil alloantigen-3a (HNA-3a; [256]). 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 [574]. 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. [463]), and polymorphisms in this gene are associated with variations in skin and hair color (e.g. [254]

SLC47 family of multidrug and toxin extrusion transporters
Transporters → SLC superfamily of solute carriers → SLC47 family of multidrug and toxin extrusion transporters Overview: These proton:organic cation exchangers are predicted to have 13 TM segments [709] and are suggested to be responsible for excretion of many drugs in the liver and kidneys.

SLC48 heme transporter
Transporters → SLC superfamily of solute carriers → SLC48 heme transporter Overview: HRG1 has been identified as a cell surface and lysosomal heme transporter [517]. In addition, evidence suggests this 4TM-containing protein associates with the V-ATPase in lysosomes [474]. Recent studies confirm its lysosomal location and demonstrate that it has an important physiological function in macrophages ingesting senescent red blood cells (erythrophagocytosis), recycling heme (released from the red cell hemoglobin) from the phagolysosome into the cytosol, where the heme is subsequently catabolized to recycle the iron [666].

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 [601], and later identified as a cell surface accumulation which exports heme from the cytosol [513]. 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 [113]. 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) [516].There are three paralogs of FLVCR1 in the human genome. FLVCR2, most similar to FLVCR1 [403], has been reported to function as a heme importer [163]. 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 [435].
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 [63].

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 [41,137]. OSTα/OSTβ is also expressed in steroidogenic cells of the brain and adrenal gland, where it may contribute to steroid movement [193]. Bile acid transport is suggested to be facilitative and inde-pendent of sodium, potassium, chloride ions or protons [41,137].  [41,137,193]. OSTα/OSTβ-mediated transport of bile salts is inhibited by clofazimine [635]. OSTα is suggested to be a seven TM pro-tein, while OSTβ is a single TM 'ancillary' protein, both of which are thought to have intracellular C-termini [400]. Both proteins function in solute transport and bimolecular fluorescence complementation studies suggest the possibility of OSTα homooligomers, as well as OSTα/OSTβ hetero-oligomers [117,400]. An inherited mutation in OSTβ is associated with congenital diarrhea in children [591].   Comments XPR1/SLC53A1 is a phosphate carrier which appears to play a role in bone and tooth mineralization. It is ubiquitously expressed [44,600]. The pathological consequences of defective SLC53A1 expression in the brain [393] and kidney [20] have been reported. Comments SLC54A1 is ubiquitously expressed [642]. SLC54A2 is ubiquitously expressed [642]. SLC54A3 is expressed in testis, postmeiotic spermatids and sperm cells [642].

SLC54 Mitochondrial pyruvate carriers
Comments: SLC54 family transporters appear to function as mechanisms for accumulating pyruvate into mitochondria to link glycolysis with oxidative phosphorylation.  [32], as discussed several years later in [205]. SFXN1 likely transports pyridoxin or another heme precursor or the 5'-aminolevulinate synthase 2 (ALAS2; P22557) cofactor [205,694]. SFXN1 has recently been suggested to be a mitochondrial serine transporter [371]. It is mainly expressed in adult kidney and liver (mouse) [205].
In mice sideroflexin 2 expression is mainly detected in adult kidney and liver [205]. In human tissues it is detected at highest levels in kidney, liver and pancreas [694].
Sideroflexin 4 is expressed in mouse kidney, brain and heart [205]. The SFXN4a isoform is most highly expressed in human kidney and pancreas, and the SFXN4b isoform is barely detectable in brain [713].
Sideroflexin 5 is expressed in mouse brain and liver [205].
Comments: These are a family of incompletely-characterised mitochondrial transporters.  [250,511] Comments Expressed in kidney, colon, heart and liver (the latter only at the mRNA level) [251]; universally expressed [714].
Expressed in the spleen, lung, testis and subcellularly in the ER [19]. Comments MFSD5/SLC61 is a putative 12TM cell-surface protein which appears to allow the accumulation of molybdate, and where the neural expression appears to respond to changes in the diet. It is expressed in cervix, stomach, nerve and skin [610]; ubiquitous but higher in skeletal muscle, olfactory bulb [212]; blood, cortex, hypothalamus, cerebellum and spinal cord (mouse) [494]. Comments ANKH/SLC62 is a putative 8TM membrane protein, also known as progressive ankylosis protein homolog. Mutations in this protein are associated with bone and joint abnormalities. It is expressed in kidney and bone [92].  [503,504], Ca 2+ , H + [144] Comments TMEM165/SLC64 is a putative 6TM intracellular membrane protein. Mutations in the protein are associated with congenital disorder of glycosylation. It has been suggested to be essential for milk production in the mammary gland [582]. TMEM165 deficiency (via siRNA knockdown) causes Golgi glycosylation defects in transfected HEK cells [211]. Selective antagonists -ezetimibe (Inhibition) (pK d 6.7) [227] Comments Expression is ubiquitous [10], with highest levels detected in liver, lung, and pancreas [136]. NPC1 plays a critical role in the regulation of intracellular cholesterol trafficking [93]. Mutations in the NPC1 gene have been identified in patients with the lipid storage disorder Niemann-Pick disease type C1 [62,93,255,686].

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. Although rat and mouse OATP1A4 are considered the orthologs of human OATP1A2 we do not cross-link to gene or protein databases for these since in reality there are five genes in rodents that arose through gene duplication in this family and it is not clear which one of these is the "true" ortholog.
Other inhibitors include, fibrates, flavonoids, glitazones and macrolide antibiotics. Estrone-3-sulphate or the drug substrates atorvastatin, pravastatin and rosuvastatin are used as a probe.
Other inhibitors include, HIV protease inhibitors, glitazones and macrolide antibiotics. CCK-8 is used as an OATP1B3-selective probe.