The Concise Guide to PHARMACOLOGY 2015/16: Transporters

The Concise Guide to PHARMACOLOGY 2015/16 provides concise overviews of the key properties of over 1750 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.13355/full. G protein‐coupled receptors 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 transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The Concise Guide is published in landscape format in order to facilitate comparison of related targets. It is a condensed version of material contemporary to late 2015, which is presented in greater detail and constantly updated on the website www.guidetopharmacology.org, superseding data presented in the previous Guides to Receptors & Channels and the Concise Guide to PHARMACOLOGY 2013/14. It is produced in conjunction with NC‐IUPHAR and provides the official IUPHAR classification and nomenclature for human drug targets, where appropriate. It consolidates information previously curated and displayed separately in IUPHAR‐DB and GRAC and provides a permanent, citable, point‐in‐time record that will survive database updates.

The second largest family of membraine proteins in the human genome, after the G protein-coupled receptors, are the SLC solute carrier family. Within the solute carrier family, there are not only a great variety of solutes transported, from simple inorganic ions to amino acids and sugars to relatively complex organic molecules like haem. The solute carrier family includes 52 families of almost 400 members. Many of these overlap in terms of the solutes that they carry. For example, amino acids accumulation is mediated by members of the SLC1, SLC3/7, SLC6, SLC15, SLC16, SLC17, SLC32, SLC36, SLC38 and SLC43 families. Further members of the SLC superfamily regulate ion fluxes at the plasma membrane, or solute transport into and out of cellular organelles. Some SLC family members remain orpahn transporters, in as much as a physiological function has yet to be dtermined. 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 3,4,6,7,8,9,10,11,12,13 or 14 TM domains. The SLC transporters include members which function as antiports, where solute movement in one direction is balanced by a solute moving in the reverse direction. Symports allow concentration gradients of one solute to allow movement of a second solute across a membrane. A third, relatively small group are equilibrative transporters, which allow solutes to travel across membranes down their concentration gradients. A more complex family of transporters, the SLC27 fatty acid transporters also express enzymatic function. Many of the transporters also express electrogenic properties of ion channels.
Family structure This is a complete listing of transporter families included in the online IUPHAR/BPS Guide to PHARMACOLOGY database. Summary information is provided here for a subset of transporters where these are of significant pharmacological interest; further transporters are listed in the database 6113 ATP Comments Loss-of-function mutations are associated with Tangier disease, in which plasma HDL cholesterol levels are greatly reduced. ABCA1 is a key player in cholesterol efflux from macrophages to lipid-free apo-A1 in a process known as reverse cholesterol transport, a role that is important in atherosclerosis. ABCA1 also controls apoE lipidation, and has a role in Alzheimer's disease, including an impact on amyloid β (APP, P05067) deposition and clearance. ABCA1 is transcriptionally regulated by Liver X Receptors (LXR) and Retinoic X Receptor (RXR), which are being explored as therapeutic targets for development of agonists for treatment of metabolic and neurodegenerative disorders [286].
Loss-of-function mutations are associated with pulmonary surfactant deficiency 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 [173]. ABCA4 facilitates the clearance of all-trans-retinal from photoreceptor disc membranes following photoexcitation. ABCA4 can also transport N-11-cis-retinylidenephosphatidylethanolamine, 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 [394].
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 [113].
Genome wide association studies identify ABCA7 variants as associated with Alzheimer's Disease [232].
Reported to play a role in skin ceramide formation [555]. 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 [171].  [290]; other subcellular localizations are possible, such as the plasma membrane, as a specific determinant of the Langereis blood group system [227].
Loss-of-function mutations are associated with Dubin-Johnson syndrome, in which plasma levels of conjugated bilirubin are elevated (OMIM: 237500).
Transports conjugates of glutathione, sulfate or glucuronide [51] Although reported to facilitate cellular cyclic nucleotide export, this role has been questioned [51]; reported to export prostaglandins in a manner sensitive to NSAIDS [403] Although reported to facilitate cellular cyclic nucleotide export, this role has been questioned [51] Loss-of-function mutations in ABCC6 are associated with pseudoxanthoma elasticum (OMIM: 264800).

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.  [208].
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 [53,406,533] reviewed by [254]). This structural data is in agreement with the proposed quaternary structure for EAAT2 [185] and several functional studies that propose the monomer is the functional unit [205,284,302,418]. Recent evidence suggests that EAAT3 and EAAT4 may assemble as heterotrimers [362]. 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 [412]. Recent evidence supports altered glutamate transport and novel roles in brain for splice variants of EAAT1 and EAAT2 [184,303]. Three patients with dicarboxylic aminoaciduria (DA) were recently found to have loss-of-function mutations in EAAT3 [24]. 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-B-mediated EAAT2 promoter activation [181,306,414] reviewed by [277]). PPARγ activation (e.g. by rosiglitazone) also leads to enhanced expression of EAAT though promoter activation [411]. In addition, several translational activators of EAAT2 have recently been described [98] along with treatments that increase the surface expression of EAAT2 (e.g. [301,554]), or prevent its down-regulation (e.g. [199]). A thermodynamically uncoupled Clflux, activated by Na + and glutamate [207,265,327] (Na + and aspartate in the case of GltPh [417]), is sufficiently large, in the instances of EAAT4 and EAAT5, to influence neuronal excitability [476,498]. 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 [176].  [141,443,444,492]. K B (or K i ) values derived in uptake assays are generally higher (e.g. [444]). In addition to acting as a poorly transportable inhibitor of EAAT2, (2S,4R)-4-methylglutamate, also known as SYM2081, is a competitive substrate for EAAT1 (K M = 54 M; [235,492]) and additionally is a potent kainate receptor agonist [548] which renders the compound unsuitable for autoradiographic localisation of EAATs [14]. Similarly, at concentrations that inhibit EAAT2, dihydrokainate binds to kainate receptors [444]. WAY-855 and WAY-213613 are both non-substrate inhibitors with a preference for EAAT2 over EAAT3 and EAAT1 [132,133]. NBI-59159 is a non-substrate inhibitor with modest selectivity for EAAT3 over EAAT1 ( 10-fold) and EAAT2 (5-fold) [99,130]. Analogously, L-β-threo-benzyl-aspartate (L-β-BA) is a competitive non-substrate inhibitor that preferentially blocks EAAT3 versus EAAT1, or EAAT2 [150].

Nomenclature
[ 3 H](2S,4R)-4-methylglutamate demonstrates low affinity binding (K D 6.0 M) to EAAT1 and EAAT2 in rat brain homogenates [15] and EAAT1 in murine astrocyte membranes [13], whereas [ 3 H]ETB-TBOA binds with high affinity to all EAATs other than EAAT3 [445]. The novel isoxazole derivative (-)-HIP-A may interact at the same site as TBOA and preferentially inhibit reverse transport of glutamate [97]. 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 [141]. 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 [165,166]. In addition to the agents listed in the 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 [16,489]. ASCT1 and ASCT2 also exhibit thermodynamically uncoupled chloride channel activity associated with substrate transport [63,541]. Whereas EAATs counter-transport K + (see above) ASCTs do not and their function is independent of the intracellular concentration of K + [541].

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

SLC7 family
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.   Comments: CAT4 appears to be non-functional in heterologous expression [516], 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 sodium-independent system L transporters. LAT1 transports large neutral amino acids including branched-chain and aromatic amino acids as well as miglustat, whereas LAT2 transports most of the neutral amino acids.
Heterodimers between 4F2hc and y + LAT1 or y + LAT2 generate transporters similar to the system y + L , which transport cationic (L-arginine, L-lysine, L-ornithine) amino acids independent of sodium and neutral (L-leucine, L-isoleucine, L-methionine, L-glutamine) amino acids in a partially sodium-dependent manner. These transporters are N-ethylmaleimide-insensitive. Heterodimers between rBAT and b 0,+ AT appear to mediate 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.

Further Reading
Bhutia YD et al.  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 [518] for an extensive review). SGLT1 is predominantly expressed in the small intestine, mediating the absorption of glucose (e.g. D-glucose), but also occurs in the brain, heart and in the late proximal straight tubule of the kidney. The expression of SGLT2 is almost exclusively restricted to the early proximal convoluted tubule of the kidney, where it is largely responsible for the renal reabsorption of glucose. SGLT3 is not a transporter but instead acts as a glucosensor generating an inwardly directed flux of Na + that causes membrane depolarization [120]. Comments: Recognition and transport of substrate by SGLTs requires that the sugar is a pyranose. De-oxyglucose derivatives have reduced affinity for SGLT1, but the replacement of the sugar equatorial hydroxyl group by fluorine at some positions, excepting C2 and C3, is tolerated (see [518] for a detailed quantification). Although SGLT1 and SGLT2 have been described as high-and low-affinity sodium glucose co-transporters, respectively, recent work suggests that they have a similar affinity for glucose under physiological conditions [236]. Selective blockers of SGLT2, and thus blocking 50% of renal glucose reabsorption, are in development for the treatment of diabetes (e.g. [80]).

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 [291]. Through recapture of choline generated by the hydrolysis of ACh by acetylcholinesterase, CHT serves to maintain acetylcholine synthesis within the presynaptic terminal [159]. 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 [158]. 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 [477].

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 ) [42]. 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 [422]. 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 [179]. 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 [179]. SMCT1 is a high-affinity transporter whereas SMCT2 is a low-affinity transporter. The physiological substrates for SMCT1 and SMCT2 are lactate (L-lactic acid and D-lactic acid), pyruvic acid, propanoic acid, and nicotinic acid in non-colonic tissues such as the kidney. SMCT1 is also likely to be the principal transporter for the absorption of nicotinic acid (vitamin B 3 ) in the intestine and kidney [197]. In the small intestine and colon, the physiological substrates for these transporters are nicotinic acid and the short-chain fatty acids acetic acid, propanoic acid, and butyric acid that are produced by bacterial fermentation of dietary fiber [350]. 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 [470]. SMCT1 also functions as a tumour suppressor in the colon as well as in various other non-colonic tissues [180]. 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 [471]; 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 [179,180,213]. 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 [451].  [123]. Lipoic acid appears to act as a competitive substrate inhibitor of SMVT [505] and the anticonvulsant drugs primidone and carbamazepine competitively block the transport of biotin by brush border vesicles prepared from human intestine [423].

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 [41]. 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 [11].

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 [442]. 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 [329]. 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 [83,219]. CT1, which transports creatine, has a ubiquitous expression pattern, often co-localizing with creatine kinase [83].
Substrates nipecotic acid, guvacine nipecotic acid, guvacine guvacine, nipecotic acid    [116]). 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 [282]. Several derivatives of exo-THPO (e.g. N-methyl-exo-THPO and N-acetyloxyethyl-exo-THPO) demonstrate selectivity as blockers of astroglial, versus neuronal, uptake of GABA [see [93,437] for reviews]. GAT3 is inhibited by physiologically relevant concentrations of Zn 2+ [96]. 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 [121]. Although inhibitors of creatine transport by CT1 (e.g. β-guanidinopropionic acid, cyclocreatine, guanidinoethane sulfonic acid) are known (e.g. [103]) they insufficiently characterized to be included in the 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 [36,152,194,459] for reviews). GlyT1 transporter isoforms expressed in glia surrounding glutamatergic synapses regulate synaptic glycine concentrations influencing NMDA receptor-mediated neurotransmission [35,175], but also are important, in early neonatal life, for regulating glycine concentrations at inhibitory glycinergic synapses [195]. Homozygous mice engineered to totally lack GlyT1 exhibit severe respiratory and motor deficiencies due to hyperactive glycinergic signalling and die within the first postnatal day [195,479]. 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 [532]. 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 [196,415]. Mice in which GlyT2 has been deleted develop a fatal hyperekplexia phenotype during the second postnatal week [196] and mutations in the human gene encoding GlyT2 (SLC6A5) have been identified in patients with hyperekplexia (reviewed by [221]). ATB 0+ (SLCA14) is a transporter for numerous dipolar and cationic amino acids and thus has a much broader substrate specificity than the glycine transporters alongside which it is grouped on the basis of structural similarity [83]. ATB 0+ is expressed in various peripheral tissues [83]. 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) [65].
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 [100,480,481].

Further Reading
Bobulescu

SLC10 family of sodium-bile acid co-transporters
Transporters SLC superfamily of solute carriers SLC10 family of sodium-bile acid co-transporters Overview: The SLC10 family transport bile acids, sulphated solutes, and other xenobiotics in a sodium-dependent manner. The founding members, SLC10A1 (NTCP) and SLC10A2 (ASBT) function, along with members of the ABC transporter family (MDR1/ABCB1, BSEP/ABCB11 and MRP2/ABCC2) and the organic solute transporter obligate heterodimer OSTα:OSTβ (SLC51), to maintain the enterohepatic circulation of bile acids [110,281]. SLC10A6 (SOAT) functions as a sodium-dependent transporter of sulphated solutes included sulfphated steroids and bile acids [187,189]. Transport function has not yet been demonstrated for the 4 remaining members of the SLC10 family, SLC10A3 (P3), SLC10A4 (P4), SLC10A5 (P5), and SLC10A7 (P7), and the identity of their endogenous substrates remain unknown [160,189,193,500]. Members of the SLC10 family are predicted to have seven transmembrane domains with an extracellular N-terminus and cytoplasmic C-terminus [29,215]. Comments chenodeoxycholyl-N¯-nitrobenzoxadiazol-lysine is a fluorescent bile acid analogue used as a probe [188,509]. --

Further Reading
Anwer dependent on proton transport. Both proteins appear to have 12 TM regions and cytoplasmic N-and C-termini. NRAMP1 is involved in antimicrobial action in macrophages, although its precise mechanism is undefined. Facilitated diffusion of divalent cations into phagosomes may increase intravesicular free radicals to damage the pathogen. Alternatively, export of divalent cations from the phagosome may deprive the pathogen of essential enzyme cofactors. SLC11A1/DMT1 is more widely expressed and appears to assist in divalent cation assimilation from the diet, as well as in phagocytotic cells. Comments: Loss-of-function mutations in NRAMP1 are associated with increased susceptibility to microbial infection (OMIM: 607948). Loss-of-function mutations in DMT1 are associated with microcytic anemia (OMIM: 206100).

SLC15 family of peptide transporters
Transporters SLC superfamily of solute carriers SLC15 family of peptide transporters Overview: The SLC15 family of peptide transporters may be divided on the basis of structural and functional differences into two subfamilies: SLC15A1 (PepT1) and SLC15A2 (PepT2) transport di-and tripeptides, but not amino acids, whereas SLC15A3 (PHT2) and SLC15A4 (PHT1) transport L-histidine and some di-and tripeptides [105]. The transporters are 12 TM proteins with intracellular termini and an extended extracellular loop at TM 9/10. The crystal structure of PepTSo (a prokaryote homologue of PepT1 and PepT2 from Shewanella oneidensis) confirms many of the predicted structural features of mammalian PepT1 and PepT2 [360]. PHT1 has been suggested to be intracellular [410], while PHT2 protein is located on lysosomes in transfected cells [52,230,426]. PHT1 is hypothesised to mediate efflux of bacterial-derived peptides into the cytosol perhaps in the colon where SLC15A4 mRNA expression is increased in inflammatory bowel disease [305]. Transport via PHT1 may be important in immune responses as both Toll-like receptor-and NOD1-mediated responses are reduced in PHT1 knockout mice or mouse strains expressing mutations in PHT1 [45,430]. Comments: The PepT1 and PepT2 transporters are particularly promiscuous in the transport of dipeptides and tripeptides from the endogenous amino acids, as well as some D-amino acid containing peptides. PepT1 has also been exploited to allow delivery of therapeutic pro-drugs, such as those for zidovudine (zidovudine) [218], sulpiride [508] and cytarabine [457]. D-Ala-Lys-AMCA has been used as a fluorescent probe to identify transport via both PepT1 and PepT2 [416] .

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. 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 [349], 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 [33]. 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 [431].

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.

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.

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 [79]. Stoichiometry Unknown

Comments
Prestin has been suggested to function as a molecular motor, rather than a transporter   [153,346,373]. 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 [344,432].

Nomenclature
Fatty acid transport protein 1 Fatty acid transport protein 2 Fatty acid transport protein 3 Systematic nomenclature SLC27A1 SLC27A2 SLC27A3 Common abreviation FATP1 FATP2 FATP3 Endogenous substrates palmitic acid oleic acid γ-linolenic acid octanoic acid [190]; arachidonic acid palmitic acid oleic acid butyric acid [432] --Nomenclature Fatty acid transport protein 4 Fatty acid transport protein 5 Fatty acid transport protein 6 Systematic nomenclature Endogenous substrates palmitic acid , oleic acid γ-linolenic acid octanoic acid [190]; palmitic acid oleic acid butyric acid, γ-linolenic acid arachidonic acid [454] palmitic acid oleic acid γ-linolenic acid octanoic acid [190] Comments FATP4 is genetically linked to restrictive dermopathy. 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 [314,429] and FATP4 [43,549], as well as bile acid inhibitors of FATP5 [549], 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. 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).

Nomenclature
Comments: ZnT8/SLC30A8 is described as a type 1 diabetes susceptibility gene. Zinc fluxes may be monitored through the use of radioisotopic Zn-65 or the fluorescent dye FluoZin 3.

Further Reading
Bouron

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 [401]. 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 [304]. Comments: Copper accumulation through CTR1 is sensitive to silver ions, but not divalent cations [304].

Further Reading
Howell

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 [182,183], and is a member of the structurally-defined amino acid-polyamine-organocation/APC clan composed of SLC32, SLC36 and SLC38 transporter families (see [435]). VIAAT was originally suggested to be composed of 10 TM segments with cytoplasmic N-and C-termini [335]. 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 [333]. 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 (½pH) and electrical (½ ) components of the proton electrochemical gradient (½ H +) established by a vacuolar H + -ATPase [335]. However, one study, [259], 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 [155,539]. VIAAT knock out mice die between embryonic day 18.5 and birth [515]. 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 [425,515]. 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 [267], which imports cytosolic acetyl CoA into these intracellular organelles. In heterologous expression studies, acetyl CoA transport through AT1 was inhibited by coenzyme A, but not acetic acid, ATP or UDP-galactose [255]. A loss-of-function mutation in ACATN1/SLC33A1 has been associated with spastic paraplegia (SPG42, [317]), although this observation could not be replicated in a subsequent study [436].

Further Reading
Hirabayashi Y et al.

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 [10]. Substrates UDP-xylose [18], UDP N-acetyl-glucosamine [18] GDP-fucose [325] UDP-N-acetylgalactosamine [354], UDP-glucuronic acid [354] UDP-N-acetylgalactosamine

Comments:
Both PAT1 and PAT2 can also function as an electroneutral transport system for H + and fatty acids including acetic acid, propanoic acid and butyric acid [164]. Loss-of-function mutations in PAT2 lead to iminoglycinuria and hyperglycinuria in man [65].

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 [435]. Substrates L-alanine L-serine, L-glutamine, L-asparagine, L-histidine, L-cysteine, L-methionine glycine, L-threonine, L-proline, L-tyrosine, L-valine [5] L-alanine, L-methionine L-asparagine, L-glutamine, L-serine, L-proline, glycine L-threonine, L-leucine, L-phenylalanine [223] L-histidine L-arginine, L-alanine, L-asparagine, L-lysine glycine, L-glutamine, L-serine, L-proline, L-leucine, L-phenylalanine [ L-asparagine, L-serine, L-histidine, L-glutamine glycine, L-alanine [359]  Comments SNAT7/SLC38A7 has been described to be a system N-like transporter allowing preferential accumulation of glutamine (e.g. L-glutamine), histidine (e.g. L-histidine) and asparagine (e.g. L-asparagine) [237].

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 [191,321]. The bicarbonate transport inhibitor DIDS has been reported to inhibit cation accumulation through ZIP14 [191].

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 [407], with the functional transporter potentially a dimeric arrangement [3,111]. Ferroportin is essential for iron homeostasis [126]. 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 anti-anemia agents. Anti-ferroportin monoclonal antibodies are such an agent.

Further Reading
McKie AT et al. 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 [287], possibly as a result of co-expression of particular protein partners (see [421]). Topological modelling suggests 10 TM domains with cytoplasmic C-and N-termini.

SLC43 family of large neutral amino acid transporters
Transporters SLC superfamily of solute carriers SLC43 family of large neutral amino acid transporters Overview: LAT3 (SLC43A1) and LAT4 (SLC43A2) are transporters with system L amino acid transporter activity, along with the structurally and functionally distinct transporters LAT1 and LAT2 that are members of the SLC7 family. LAT3 and LAT4 contain 12 putative TM domains with both N and C termini located intracellularly. They transport neutral amino acids in a manner independent of Na + and Cland with two kinetic components [22,47]. LAT3/SLC43A1 is expressed in human tissues at high levels in the pancreas, liver, skeletal muscle and fetal liver [22] whereas LAT4/SLC43A2 is primarily expressed in the placenta, kidney and peripheral blood leukocytes [47]. SLC43A3 is expressed in vascular endothelial cells [502] but remains to be characterised. Overview: Based on the proptypical member of this family, PCFT, this family includes proton-driven transporters with 11 TM segments. SLC46A1 has been described to act as an intestinal proton-coupled high-affinity folic acid transporter [393], with lower affinity for heme. Folic acid accumulation is independent of Na + or K + ion concentrations, but driven by extracellular protons with an as yet undefined stoichiometry. Comments Loss-of-function mutations in PCFT (SLC46A1) are the molecular basis for hereditary folate maladsorption [428].

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 [545] 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 [398]. In addition, evidence suggests this 4TM-containing protein associates with the V-ATPase in lysosomes [367]. 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 [511].

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 [464], and later identified as a cell surface accumulation which exports heme from the cytosol [395]. 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 [89]. FLVCR-mediated heme transport is essential for erythropoiesis. Flvcr1 gene mutations have been identified as the cause of PCARP (posterior column ataxia with retinitis pigmentosa (PCARP) [397].There are three paralogs of FLVCR1 in the human genome. FLVCR2, most similar to FLVCR1 [319], has been reported to function as a heme importer [129]. 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 [340]. 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 [46]. Substrates heme [395] heme [129] Stoichiometry Unknown

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 bile duct, small intestine and kidney, and elsewhere, as part of the enterohepatic circulation [28,109]. OSTα/OSTβ is also expressed in steroidogenic cells of the brain and adrenal gland, where it may contribute to steroid movement [154]. Bile acid transport is suggested to be facilitative and independent of sodium, potassium, chloride ions or protons [28,109].  [28,109,154]. 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 [315]. Bimolecular fluorescence complementation studies suggest the possibility of OSTα homo-oligomers, as well as OSTα/OSTβ hetero-oligomers [92,315].

Nomenclature
Organic solute transporter subunit α Organic solute transporter subunit β   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.