THE CONCISE GUIDE TO PHARMACOLOGY 2017/18: Transporters

1The authors state that there are no conflicts of interest to declare.

2The majority of biological solutes are charged organic or inorganic molecules. Cellular membranes are hydrophobic and, therefore, effective barriers to separate them allowing the formation of gradients, which can be exploited, for example, in the generation of energy. Membrane transporters carry solutes across cell membranes, which would otherwise be impermeable to them. The energy required for active transport processes is obtained from ATP turnover or by exploiting ion gradients.

3ATP‐driven transporters can be divided into three major classes: P‐type ATPases; F‐type or V‐type ATPases and ATP‐binding cassette transporters. The first of these, P‐type ATPases, are multimeric proteins, which transport (primarily) inorganic cations. The second, F‐type or V‐type ATPases, are proton‐coupled motors, which can function either as transporters or as motors. Last, are ATP‐binding cassette transporters, heavily involved in drug disposition as well as transporting endogenous solutes.

4The 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 orphan 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 domain protein. Membrane topology predictions for other families suggest 3,4,6,7,8,9,10,11,12,13 or 14 TM domains. The SLC transporters include members which function as antiports, where solute movement in one direction is balanced by a solute moving in the reverse direction. Symports allow concentration gradients of one solute to allow movement of a second solute across a membrane. A third, relatively small group are equilibrative transporters, which allow solutes to travel across membranes down their concentration gradients. A more complex family of transporters, the SLC27 fatty acid transporters also express enzymatic function. Many of the transporters also express electrogenic properties of ion channels.

5S362 ATP‐binding cassette transporter family

6S362 ABCA subfamily

7S363 ABCB subfamily

8S364 ABCC subfamily

9S366 ABCD subfamily of peroxisomal ABC transporters

10S367 ABCG subfamily

11S368 F‐type and V‐type ATPases

12S368 F‐type ATPase

13S368 V‐type ATPase

14S368 P‐type ATPases

15S369 Na+/K+‐ATPases

16S369 Ca2+‐ATPases

17S369 H+/K+‐ATPases

18S370 Cu+‐ATPases

19S370 Phospholipid‐transporting ATPases

20S371 Major facilitator superfamily (MFS) of transporters

21S371 SLC superfamily of solute carriers

22S372 SLC1 family of amino acid transporters

23S372 Glutamate transporter subfamily

24S374 Alanine/serine/cysteine transporter subfamily

25S375 SLC2 family of hexose and sugar alcohol transporters

26S375 Class I transporters

27S375 Class II transporters

28S376 Proton‐coupled inositol transporter

29S377 SLC3 and SLC7 families of heteromeric amino acid transporters (HATs)

30S377 SLC3 family

31S378 SLC7 family

32S379 SLC4 family of bicarbonate transporters

33S379 Anion exchangers

34S380 Sodium‐dependent HCO 3− transporters

35S381 SLC5 family of sodium‐dependent glucose transporters

36S381 Hexose transporter family

37S382 Choline transporter

38S383 Sodium iodide symporter, sodium‐dependent multivitamin transporter and sodium‐coupled monocarboxylate transporters

39S384 Sodium myo‐inositol cotransporter transporters

40S385 SLC6 neurotransmitter transporter family

41S385 Monoamine transporter subfamily

42S386 GABA transporter subfamily

43S387 Glycine transporter subfamily

44S389 Neutral amino acid transporter subfamily

45S390 SLC8 family of sodium/calcium exchangers

46S390 SLC9 family of sodium/hydrogen exchangers

47S391 SLC10 family of sodium‐bile acid co‐transporters

48S392 SLC11 family of proton‐coupled metal ion transporters

49S392 SLC12 family of cation‐coupled chloride transporters

50S394 SLC13 family of sodium‐dependent sulphate/carboxylate transporters

51S395 SLC14 family of facilitative urea transporters

52S396 SLC15 family of peptide transporters

53S397 SLC16 family of monocarboxylate transporters

54S399 SLC17 phosphate and organic anion transporter family

55S399 Type I sodium‐phosphate co‐transporters

56S399 Sialic acid transporter

57S400 Vesicular glutamate transporters (VGLUTs)

58S401 Vesicular nucleotide transporter

59S401 SLC18 family of vesicular amine transporters

60S402 SLC19 family of vitamin transporters

61S403 SLC20 family of sodium‐dependent phosphate transporters

62S304 SLC22 family of organic cation and anion transporters

63S304 Organic cation transporters (OCT)

64S405 Organic zwitterions/cation transporters (OCTN)

65S406 Organic anion transporters (OATs)

66S407 Urate transporter

67– Orphan or poorly characterized SLC22 family members

68S407 SLC23 family of ascorbic acid transporters

69S408 SLC24 family of sodium/potassium/calcium exchangers

70S409 SLC25 family of mitochondrial transporters

71S409 Mitochondrial di‐ and tri‐carboxylic acid transporter subfamily

72S410 Mitochondrial amino acid transporter subfamily

73S412 Mitochondrial phosphate transporters

74S412 Mitochondrial nucleotide transporter subfamily

75S413 Mitochondrial uncoupling proteins

76S414 Miscellaneous SLC25 mitochondrial transporters

77S414 SLC26 family of anion exchangers

78S414 Selective sulphate transporters

79S415 Chloride/bicarbonate exchangers

80S415 Anion channels

81S416 Other SLC26 anion exchangers

82S416 SLC27 family of fatty acid transporters

83S418 SLC28 and SLC29 families of nucleoside transporters

84S418 SLC28 family

85S418 SLC29 family

86S420 SLC30 zinc transporter family

87S421 SLC31 family of copper transporters

88S421 SLC32 vesicular inhibitory amino acid transporter

89S422 SLC33 acetylCoA transporter

90S423 SLC34 family of sodium phosphate co‐transporters

91S424 SLC35 family of nucleotide sugar transporters

92S425 SLC36 family of proton‐coupled amino acid transporters

93S426 SLC37 family of phosphosugar/phosphate exchangers

94S427 SLC38 family of sodium‐dependent neutral amino acid transporters

95S427 System A‐like transporters

96S428 System N‐like transporters

97S428 Orphan SLC38 transporters

98S429 SLC39 family of metal ion transporters

99S429 SLC40 iron transporter

100S430 SLC41 family of divalent cation transporters

101S431 SLC42 family of Rhesus glycoprotein ammonium transporters

102S432 SLC43 family of large neutral amino acid transporters

103S432 SLC44 choline transporter‐like family

104S433 SLC45 family of putative sugar transporters

105S434 SLC46 family of folate transporters

106S435 SLC47 family of multidrug and toxin extrusion transporters

107S436 SLC48 heme transporter

108S436 SLC49 family of FLVCR‐related heme transporters

109S437 SLC50 sugar transporter

110S437 SLC51 family of steroid‐derived molecule transporters

111S438 SLC52 family of riboflavin transporters

112S439 SLCO family of organic anion transporting polypeptides

113S441 Patched family

114ATP‐binding cassette transporters are ubiquitous membrane proteins characterized by active ATP‐dependent movement of a range of substrates, including ions, lipids, peptides, steroids. Individual subunits are typically made up of two groups of 6TM‐spanning domains, with two nucleotide‐binding domains (NBD). The majority of eukaryotic ABC transporters are ŚfullŠ transporters incorporating both TM and NBD entities. Some ABCs, notably the ABCD and ABCG families are half‐transporters with only a single membrane spanning domain and one NBD, and are only functional as homo‐ or heterodimers. Eukaryotic ABC transporters convey substrates from the cytoplasm, either out of the cell or into intracellular organelles. Their role in the efflux of exogenous compounds, notably chemotherapeutic agents, has led to considerable interest.

115A number of structural analogues are not found in man: Abca14 (ENSMUSG00000062017); Abca15 (ENSMUSG00000054746); Abca16 (ENSMUSG00000051900) and Abca17 (ENSMUSG0000 0035435).

116ABCC7 (also known as CFTR, a 12TM ABC transporter‐type protein, is a cAMP‐regulated epithelial cell membrane Cl‐ channel involved in normal fluid transport across various epithelia and can be viewed in the Chloride channels section of the Guide. ABCC8 (ENSG00000006071, also known as SUR1, sulfonylurea receptor 1) and ABCC9 (ENSG00000069431, also known as SUR2, sulfonylurea receptor 2) are unusual in that they lack transport capacity but regulate the activity of particular K+ channels (Kir6.1‐6.2), conferring nucleotide sensitivity to these channels to generate the canonical KATP channels. ABCC13 (ENSG00000155288) is a possible pseudogene.

117This family of 'half‐transporters' act as homo‐ or heterodimers to transport various metabolites across the peroxisomal membrane, whcih include: very long‐chain fatty acid‐CoA esters, pristanic acid, di‐ and trihydroxycholestanoic acid, dicarboxylic acids and tetracosahexaenoic acid [299].

118ABCD4 (ENSG00000119688, also known as PMP69, PXMP1‐L or P70R) is located at the lysosome and is in involved in the transport of vitamin B12 (cobalamin) from lysosomes into the cytosol [105].

119This family of ‘half‐transporters’ act as homo‐ or heterodimers; particularly ABCG5 and ABCG8 are thought to be obligate heterodimers. The ABCG5/ABCG heterodimer sterol transporter structure has been determined [616], suggesting an extensive intracellular nucleotide binding domain linked to the transmembrane domains by a fold in the primary sequence. The functional ABCG2 transporter appears to be a homodimer with structural similarities to the ABCG5/ABCG8 heterodimer [617].

120A further group of ABC transporter‐like proteins have been identified to lack membrane spanning regions and are not believed to be functional transporters, but appear to have a role in protein translation [98, 434]: ABCE1(P61221, also known as OABP or 2'‐5' oligoadenylate‐binding protein); ABCF1(Q8NE71, also known as ABC50 or TNF‐α‐stimulated ABC protein); ABCF2(Q9UG63, also known as iron‐inhibited ABC transporter 2) and ABCF3(Q9NUQ8).

121Baker A et al. (2015) Peroxisomal ABC transporters: functions and mechanism. Biochem Soc Trans 43: 959‐65 [PMID:26517910]

122Beis, K. (2015) Structural basis for the mechanism of ABC transporters. Biochem Soc Trans 43: 889‐93 [PMID:26517899]

123Chen Z et al. (2016) Mammalian drug efflux transporters of the ATP binding cassette (ABC) family in multidrug resistance: A review of the past decade. Cancer Lett 370: 153‐64 [PMID:26499806]

124Kemp S et al. (2011) Mammalian peroxisomal ABC transporters: from endogenous substrates to pathology and clinical significance. Br. J. Pharmacol. 164: 1753‐66 [PMID:21488864]

125Kerr ID et al. (2011) The ABCG family of membrane‐associated transporters: you don't have to be big to be mighty. Br. J. Pharmacol. 164: 1767‐79 [PMID:21175590]

126Kloudova A et al. (2017) The Role of Oxysterols in Human Cancer. Trends Endocrinol Metab 28: 485‐496 [PMID:28410994]

127López‐Marqués RL et al. (2015) Structure and mechanism of ATP‐dependent phospholipid transporters. Biochim. Biophys. Acta 1850: 461‐475 [PMID:24746984]

128Neul C et al. (2016) Impact of Membrane Drug Transporters on Resistance to Small‐Molecule Tyrosine Kinase Inhibitors. Trends Pharmacol Sci 37: 904‐932 [PMID:27659854]

129Pena‐Solorzano D. (2016) ABCG2/BCRP: Specific and Nonspecific Modulators. Med Res Rev [PMID:28005280]

130Vauthier V et al. (2017) Targeted pharmacotherapies for defective ABC transporters. Biochem Pharmacol 136: 1‐11 [PMID:28245962]

131The F‐type (ATP synthase) and the V‐type (vacuolar or vesicular proton pump) ATPases, although having distinct subcellular locations and roles, exhibit marked similarities in subunit structure and mechanism. They are both composed of a ‘soluble’ complex (termed F1 or V1) and a membrane complex (Fo or Vo). Within each ATPase complex, the two individual sectors appear to function as connected opposing rotary motors, coupling catalysis of ATP synthesis or hydrolysis to proton transport. Both the F‐type and V‐type ATPases have been assigned enzyme commission number E.C. 3.6.3.14

132The F‐type ATPase, also known as ATP synthase or ATP phosphohydrolase (H+‐transporting), is a mitochondrial membrane‐associated multimeric complex consisting of two domains, an F0 channel domain in the membrane and an F1 domain extending into the lumen. Proton transport across the inner mitochondrial membrane is used to drive the synthesis of ATP, although it is also possible for the enzyme to function as an ATPase. The ATP5O subunit (oligomycin sensitivity‐conferring protein, OSCP, (P48047)), acts as a connector between F1 and F0 motors.

133The F1 motor, responsible for ATP turnover, has the subunit composition α3β3γ δ ϵ.

134The F0 motor, responsible for ion translocation, is complex in mammals, with probably nine subunits centring on A, B, and C subunits in the membrane, together with D, E, F2, F6, G2 and 8 subunits. Multiple pseudogenes for the F0 motor proteins have been defined in the human genome.

135Information on members of this family may be found in the online database.

136The V‐type ATPase is most prominently associated with lysosomes in mammals, but also appears to be expressed on the plasma membrane and neuronal synaptic vesicles.

137The V1 motor, responsible for ATP turnover, has eight subunits with a composition of A‐H.

138TheV0 motor, responsible for ion translocation, has six subunits (a‐e).

139Information on members of this family may be found in the online database.

140Brandt K et al. (2015) Hybrid rotors in F1F(o) ATP synthases: subunit composition, distribution, and physiological significance. Biol Chem 396: 1031‐42 [PMID:25838297]

141Krah A. (2015) Linking structural features from mitochondrial and bacterial F‐type ATP synthases to their distinct mechanisms of ATPase inhibition. Prog Biophys Mol Biol 119: 94‐102 [PMID:26140992]

142Marshansky V et al. (2014) Eukaryotic V‐ATPase: novel structural findings and functional insights. Biochim Biophys Acta 1837: 857‐79 [PMID:24508215]

143Noji H et al. (2017) Catalytic robustness and torque generation of the F1‐ATPase. Biophys Rev 9: 103‐118 [PMID:28424741]

144Okuno D et al. (2013) Single‐molecule analysis of the rotation of F(1)‐ATPase under high hydrostatic pressure. Biophys J 105: 1635‐42 [PMID:24094404]

145Phosphorylation‐type ATPases (EC 3.6.3.‐) are associated with membranes and the transport of ions or phospholipids. Characteristics of the family are the transient phosphorylation of the transporters at an aspartate residue and the interconversion between E1 and E2 conformations in the activity cycle of the transporters, taken to represent ‘half‐channels’ facing the cytoplasm and extracellular/luminal side of the membrane, respectively.

146Sequence analysis across multiple species allows the definition of five subfamilies, P1‐P5. The P1 subfamily includes heavy metal pumps, such as the copper ATPases. The P2 subfamily includes calcium, sodium/potassium and proton/potassium pumps. The P4 and P5 subfamilies include putative phospholipid flippases.

147The cell‐surface Na+/K+‐ATPase is an integral membrane protein which regulates the membrane potential of the cell by maintaining gradients of Na+ and K+ ions across the plasma membrane, also making a small, direct contribution to membrane potential, particularly in cardiac cells. For every molecule of ATP hydrolysed, the Na+/K+‐ATPase extrudes three Na+ ions and imports two K+ ions. The active transporter is a heteromultimer with incompletely defined stoichiometry, possibly as tetramers of heterodimers, each consisting of one of four large, ten TM domain catalytic α subunits and one of three smaller, single TM domain glycoprotein β‐subunits (see table). Additional protein partners known as FXYD proteins (e.g. FXYD2, P54710) appear to associate with and regulate the activity of the pump.

148Information on members of this family may be found in the online database.

149Na+/K+‐ATPases are inhibited by ouabain and cardiac glycosides, such as digoxin, as well as potentially endogenous cardiotonic steroids [29].

150The sarcoplasmic/endoplasmic reticulum Ca2+‐ATPase (SERCA) is an intracellular membrane‐associated pump for sequestering calcium from the cytosol into intracellular organelles, usually associated with the recovery phase following excitation of muscle and nerves.

151The plasma membrane Ca2+‐ATPase (PMCA) is a cell‐surface pump for extruding calcium from the cytosol, usually associated with the recovery phase following excitation of cells. The active pump is a homodimer, each subunit of which is made up of ten TM segments, with cytosolic C‐ and N‐termini and two large intracellular loops.

152Secretory pathway Ca2+‐ATPases (SPCA) allow accumulation of calcium and manganese in the Golgi apparatus.

153Information on members of this family may be found in the online database.

154The fungal toxin ochratoxin A has been described to activate SERCA in kidney microsomes [99]. Cyclopiazonic acid [482], thapsigargin[359] and BHQ are widely employed to block SERCA. Thapsigargin has also been described to block the TRPV1 vanilloid receptor [535].

155The stoichiometry of flux through the PMCA differs from SERCA, with the PMCA transporting 1 Ca2+ while SERCA transports 2 Ca2+.

156Loss‐of‐function mutations in SPCA1 appear to underlie Hailey‐Hailey disease [256].

157The H+/K+ ATPase is a heterodimeric protein, made up of α and β subunits. The α subunit has 10 TM domains and exhibits catalytic and pore functions, while the β subunit has a single TM domain, which appears to be required for intracellular trafficking and stabilising the α subunit. The ATP4A and ATP4B subunits are expressed together, while the ATP12A subunit is suggested to be expressed with the β1 (ATP1B1) subunit of the Na+/K+‐ATPase [422].

158Information on members of this family may be found in the online database.

159The gastric H+/K+‐ATPase is inhibited by proton pump inhibitors used for treating excessive gastric acid secretion, including dexlansoprazole and a metabolite of esomeprazole.

160Copper‐transporting ATPases convey copper ions across cell‐surface and intracellular membranes. They consist of eight TM domains and associate with multiple copper chaperone proteins (e.g. ATOX1, O00244).

161Information on members of this family may be found in the online database.

162These transporters are thought to translocate the aminophospholipids phosphatidylserine and phosphatidylethanolamine from one side of the phospholipid bilayer to the other to generate asymmetric membranes. They are also proposed to be involved in the generation of vesicles from intracellular and cell‐surface membranes.

163Information on members of this family may be found in the online database.

164Loss‐of‐function mutations in ATP8B1 are associated with type I familial intrahepatic cholestasis.

165A further series of structurally‐related proteins have been identified in the human genome, with as yet undefined function, including ATP13A1 (Q9HD20), ATP13A2 (Q9NQ11), ATP13A3 (Q9H7F0), ATP13A4 (Q4VNC1) and ATP13A5(Q4VNC0).

166Aperia A et al. (2016) Na+‐K+‐ATPase, a new class of plasma membrane receptors. Am J Physiol Cell Physiol 310: C491‐5 [PMID:26791490]

167Brini M et al. (2017) The plasma membrane calcium pumps: focus on the role in (neuro)pathology. Biochem Biophys Res Commun 483: 1116‐1124 [PMID:27480928]

168Bruce, JIE. (2017) Metabolic regulation of the PMCA: Role in cell death and survival. Cell Calcium [PMID:28625348]

169Diederich M. (2017) Cardiac glycosides: From molecular targets to immunogenic cell death. Biochem Pharmacol 125: 1‐11 [PMID:27553475]

170Dubois C et al. (2016) CThe calcium‐signaling toolkit: Updates needed. Biochim Biophys Acta 1863: 1337‐43 [PMID:26658643]

171Krebs J. (2015) The plethora of PMCA isoforms: Alternative splicing and differential expression. Biochim Biophys Acta 1853: 2018‐24 [PMID:25535949]

172Little R et al. (2016) Plasma membrane calcium ATPases (PMCAs) as potential targets for the treatment of essential hypertension. Pharmacol Ther 159: 23‐34 [PMID:26820758]

173Lopez‐Marques RL et al. (2015) Structure and mechanism of ATP‐dependent phospholipid transporters. Biochim Biophys Acta 1850: 461‐75 [PMID:24746984]

174Migocka M. (2015) Copper‐transporting ATPases: The evolutionarily conserved machineries for balancing copper in living systems. IUBMB Life 67: 737‐45 [PMID:26422816]

175Padanyi R et al. (2016) Multifaceted plasma membrane Ca(2+) pumps: From structure to intracellular Ca(2+) handling and cancer. Biochim Biophys Acta 1863: 1351‐63 [PMID:26707182]

176Pomorski TG et al. (2016) Lipid somersaults: Uncovering the mechanisms of protein‐mediated lipid flipping. Prog Lipid Res 64: 69‐84 [PMID:27528189]

177Retamales‐Ortega R et al. (2016) P2C‐Type ATPases and Their Regulation. Mol Neurobiol 53: 1343‐54 [PMID:25631710]

178Strehler EE. (2015) Plasma membrane calcium ATPases: From generic Ca(2+) sump pumps to versatile systems for fine‐tuning cellular Ca(2.). Biochem. Biophys. Res. Commun. 460: 26‐33 [PMID:25998731]

179Tadini‐Buoninsegni F et al. (2017) Mechanisms of charge transfer in human copper ATPases ATP7A and ATP7B. IUBMB Life 69: 218‐225 [PMID:28164426]

180The Major Facilitator superfamily (MFS) of transporters was initially characterised as prokaryotic sugar transporters.

181Loscher, W et al. (2016) Synaptic Vesicle Glycoprotein 2A Ligands in the Treatment of Epilepsy and Beyond. CNS Drugs 30: 1055‐1077 [PMID:27752944]

182Mendoza‐Torreblanca, JG et al. (2013) Synaptic vesicle protein 2A: basic facts and role in synaptic function. Eur J Neurosci 38: 3529‐39 [PMID:24102679]

183The 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.

18448 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.

185Within 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.

186Bhutia, YD et al. (2016) SLC transporters as a novel class of tumour suppressors: identity, function and molecular mechanisms. Biochem J 473: 1113‐24 [PMID:27118869]

187Cesar‐Razquin, et al. (2015) A Call for Systematic Research on Solute Carriers. Cell 162: 478‐87 [PMID:26232220]

188Colas, C et al. (2016) SLC Transporters: Structure, Function, and Drug Discovery. Medchemcomm 7: 1069‐1081 [PMID:27672436]

189Lin, L et al. (2015) SLC transporters as therapeutic targets: emerging opportunities. Nat Rev Drug Discov 14: 543‐60 [PMID:26111766]

190Nalecz, KA. (2017) Solute Carriers in the Blood‐Brain Barier: Safety in Abundance. Neurochem Res 42: 795‐809 [PMID:27503090]

191Neul, C et al. (2016) Impact of Membrane Drug Transporters on Resistance to Small‐Molecule Tyrosine Kinase Inhibitors. Trends Pharmacol Sci 37: 904‐932 [PMID:27659854]

192Nigam, SK. (2015) What do drug transporters really do? Nat Rev Drug Discov 14: 29‐44 [PMID:25475361]

193Pedersen, NB et al. (2016) Glycosylation of solute carriers: mechanisms and functional consequences. Pflugers Arch 468: 159‐76 [PMID:26383868]

194Perland, E et al. (2017) Classification Systems of Secondary Active Transporters. Trends Pharmacol Sci 38: 305‐315 [PMID:27939446]

195Rives, ML et al. (2017) Potentiating SLC transporter activity: Emerging drug discovery opportunities. Biochem Pharmacol 135: 1‐11 [PMID:28214518]

196The SLC1 family of sodium dependent transporters includes the plasma membrane located glutamate transporters and the neutral amino acid transporters ASCT1 and ASCT2 [8, 40, 301, 302, 432].

197Glutamate transporters present the unusual structural motif of 8TM segments and 2 re‐entrant loops [225]. The crystal structure of a glutamate transporter homologue (GltPh) from Pyrococcus horikoshii supports this topology and indicates that the transporter assembles as a trimer, where each monomer is a functional unit capable of substrate permeation [57, 447, 589] reviewed by [281]). This structural data is in agreement with the proposed quaternary structure for EAAT2 [203] and several functional studies that propose the monomer is the functional unit [222, 315, 332, 459]. Recent evidence suggests that EAAT3 and EAAT4 may assemble as heterotrimers [402]. The activity of glutamate transporters located upon both neurones (predominantly EAAT3, 4 and 5) and glia (predominantly EAAT 1 and 2) serves, dependent upon their location, to regulate excitatory neurotransmission, maintain low ambient extracellular concentrations of glutamate (protecting against excitotoxicity) and provide glutamate for metabolism including the glutamate‐glutamine cycle. The Na+/K+‐ATPase that maintains the ion gradients that drive transport has been demonstrated to co‐assemble with EAAT1 and EAAT2 [453]. Recent evidence supports altered glutamate transport and novel roles in brain for splice variants of EAAT1 and EAAT2 [202, 333]. Three patients with dicarboxylic aminoaciduria (DA) were recently found to have loss‐of‐function mutations in EAAT3 [29]. DA is characterized by excessive excretion of the acidic amino acids glutamate and aspartate and EAAT3 is the predominant glutamate/aspartate transporter in the kidney. Enhanced expression of EAAT2 resulting from administration of β‐lactam antibiotics (e.g. ceftriaxone) is neuroprotective and occurs through NF‐κB‐mediated EAAT2 promoter activation [197, 337, 456] reviewed by [304]). PPARγ activation (e.g. by rosiglitazone) also leads to enhanced expression of EAAT though promoter activation [452]. In addition, several translational activators of EAAT2 have recently been described [108] along with treatments that increase the surface expression of EAAT2 (e.g. [331, 615]), or prevent its down‐regulation (e.g. [216]). A thermodynamically uncoupled Cl‐ flux, activated by Na+ and glutamate [224, 291, 362] (Na+ and aspartate in the case of GltPh [458]), is sufficiently large, in the instances of EAAT4 and EAAT5, to influence neuronal excitability [527, 552]. Indeed, it has recently been suggested that the primary function of EAAT5 is as a slow anion channel gated by glutamate, rather than a glutamate transporter [192].

198The KB (or Ki) values reported, unless indicated otherwise, are derived from transporter currents mediated by EAATs expressed in voltage‐clamped Xenopus laevis oocytes [153, 487, 488, 545]. KB (or Ki) values derived in uptake assays are generally higher (e.g. [488]). In addition to acting as a poorly transportable inhibitor of EAAT2, (2S,4R)‐4‐methylglutamate, also known as SYM2081, is a competitive substrate for EAAT1 (KM= 54μM; [257, 545]) and additionally is a potent kainate receptor agonist [607] which renders the compound unsuitable for autoradiographic localisation of EAATs [19]. Similarly, at concentrations that inhibit EAAT2, dihydrokainate binds to kainate receptors [504]. WAY‐855 and WAY‐213613 are both non‐substrate inhibitors with a preference for EAAT2 over EAAT3 and EAAT1 [144, 145]. NBI‐59159 is a non‐substrate inhibitor with modest selectivity for EAAT3 over EAAT1 (>10‐fold) and EAAT2 (5‐fold) [115, 142]. Analogously, L‐β‐threo‐benzyl‐aspartate (L‐β‐BA) is a competitive non‐substrate inhibitor that preferentially blocks EAAT3 versus EAAT1, or EAAT2 [162]. [3H]SYM2081 demonstrates low affinity binding (KD≅ 6.0 μM) to EAAT1 and EAAT2 in rat brain homogenates [20] and EAAT1 in murine astrocyte membranes [18], whereas [3H]ETB‐TBOA binds with high affinity to all EAATs other than EAAT3 [489]. The novel isoxazole derivative (‐)‐HIP‐A may interact at the same site as TBOA and preferentially inhibit reverse transport of glutamate [107]. Threo‐3‐methylglutamate induces substrate‐like currents at EAAT4, but does not elicit heteroexchange of [3H]‐aspartate in synaptosome preparations, inconsistent with the behaviour of a substrate inhibitor [153]. Parawixin 1, a compound isolated from the venom from the spider Parawixia bistriata is a selective enhancer of the glutamate uptake through EAAT2 but not through EAAT1 or EAAT3 [181, 182]. In addition to the agents listed in the table, DL‐threo‐β‐hydroxyaspartate and L‐trans‐2,4‐pyrolidine dicarboxylate act as non‐selective competitive substrate inhibitors of all EAATs. Zn2+ and arachidonic acid are putative endogenous modulators of EAATs with actions that differ across transporter subtypes (reviewed by [544]).

199ASC transporters mediate Na+‐dependent exchange of small neutral amino acids such as Ala, Ser, Cys and Thr and their structure is predicted to be similar to that of the glutamate transporters [22, 540]. ASCT1 and ASCT2 also exhibit thermodynamically uncoupled chloride channel activity associated with substrate transport [67, 598]. Whereas EAATs counter‐transport K+ (see above) ASCTs do not and their function is independent of the intracellular concentration of K+[598].

200The substrate specificity of ASCT1 may extend to L‐proline and trans‐4‐hydroxy‐proline[425]. At low pH ( ˜ 5.5) both ASCT1 and ASCT2 are able to exchange acidic amino acids such as L‐cysteate and glutamate [513, 540]. In addition to the inhibitors tabulated above, HgCl2, methylmercury and mersalyl, at low micromolar concentrations, non‐competitively inhibit ASCT2 by covalent modificiation of cysteine residues [412].

201Bjorn‐Yoshimoto WE et al. (2016) The importance of the excitatory amino acid transporter 3 (EAAT3). Neurochem Int 98: 4‐18 [PMID:27233497]

202Fahlke C et al. (2016) Molecular physiology of EAAT anion channels. Pflugers Arch 468: 491‐502 [PMID:26687113]

203Fontana AC et al. (2015) Current approaches to enhance glutamate transporter function and expression. J Neurochem 134: 982‐1007 [PMID:26096891]

204Grewer C et al. (2014) SLC1 glutamate transporters. Pflugers Arch. 466: 3‐24 [PMID:24240778]

205Jensen AA et al. (2015) Excitatory amino acid transporters: recent insights into molecular mechanisms, novel modes of modulation and new therapeutic possibilities. Curr Opin Pharmacol 20: 116‐23 [PMID:25466154]

206Kanai Y et al. (2013) The SLC1 high‐affinity glutamate and neutral amino acid transporter family. Mol. Aspects Med. 34: 108‐20 [PMID:23506861]

207Takahashi K et al. (2015) Glutamate transporter EAAT2: regulation, function, and potential as a therapeutic target for neurological and psychiatric disease. Cell Mol Life Sci 72: 3489‐506 [PMID:26033496]

208The 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.

209Class I transporters are able to transport D‐glucose, but not D‐fructose, in the direction of the concentration gradient and may be inhibited non‐selectively by phloretin and cytochalasin B. GLUT1 is the major glucose transporter in brain, placenta and erythrocytes, GLUT2 is found in the pancreas, liver and kidneys, GLUT3 is neuronal and placental, while GLUT4 is the insulin‐responsive transporter found in skeletal muscle, heart and adipose tissue. GLUT14 appears to result from gene duplication of GLUT3 and is expressed in the testes [577].

210Class II transporters transport D‐fructose and appear to be insensitive to cytochalasin B. Class II transporters appear to be predominantly intracellularly located.

211Proton‐coupled inositol transporters are expressed predominantly in the brain and can be inhibited by phloretin and cytochalasin B[537].

212Augustin R. (2010) The protein family of glucose transport facilitators: It's not only about glucose after all. IUBMB Life 62: 315‐33 [PMID:20209635]

213Klip A et al. (2014) Signal transduction meets vesicle traffic: the software and hardware of GLUT4 translocation. Am. J. Physiol., Cell Physiol. 306: C879‐86 [PMID:24598362]

214Leney SE et al. (2009) The molecular basis of insulin‐stimulated glucose uptake: signalling, trafficking and potential drug targets. J. Endocrinol. 203: 1‐18 [PMID:19389739]

215Mueckler M et al. (2013) The SLC2 (GLUT) family of membrane transporters. Mol. Aspects Med. 34: 121‐38 [PMID:23506862]

216Uldry M et al. (2004) The SLC2 family of facilitated hexose and polyol transporters. Pflugers Arch. 447: 480‐9 [PMID:12750891]

217The SLC3 and SLC7 families combine to generate functional transporters, where the subunit composition is a disulphide‐linked combination of a heavy chain (SLC3 family) with a light chain (SLC7 family).

218SLC3 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.

219Information on members of this family may be found in the online database.

220SLC7 family members may be divided into two major groups: cationic amino acid transporters (CATs) and glycoprotein‐associated amino acid transporters (gpaATs).

221Cationic 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.

222CAT4 appears to be non‐functional in heterologous expression [571], while SLC7A14 has yet to be characterized.

223Glycoprotein‐associated amino acid transporters are 12 TM proteins, which heterodimerize with members of the SLC3 family to act as cell‐surface amino acid exchangers.

224Heterodimers 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.

225Heterodimers between 4F2hc and y+LAT1 or y+LAT2 generate transporters similar to the system y+L, which transport cationic (L‐arginine, L‐lysine, L‐ornithine) amino acids independent of sodium and neutral (L‐leucine, L‐isoleucine, L‐methionine, L‐glutamine) amino acids in a partially sodium‐dependent manner. These transporters are N‐ethylmaleimide‐insensitive. Heterodimers between rBAT and b0,+AT appear to mediate sodium‐independent system b0,+ transport of most of the neutral amino acids and cationic amino acids (L‐arginine, L‐lysine and L‐ornithine).

226Asc‐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.

227xCT generates a heterodimer with 4F2hc for a system x‐ e‐c transporter that mediates the sodium‐independent exchange of L‐cystine and L‐glutamic acid.

228AGT 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.

229Bhutia YD et al. (2015) Amino Acid transporters in cancer and their relevance to "glutamine addiction": novel targets for the design of a new class of anticancer drugs. Cancer Res. 75: 1782‐8 [PMID:25855379]

230Fotiadis D et al. (2013) The SLC3 and SLC7 families of amino acid transporters. Mol. Aspects Med. 34: 139‐58 [PMID:23506863]

231Palacín M et al. (2004) The ancillary proteins of HATs: SLC3 family of amino acid transporters. Pflugers Arch. 447: 490‐4 [PMID:14770309]

232Palacín M et al. (2005) The genetics of heteromeric amino acid transporters. Physiology (Bethesda) 20: 112‐24 [PMID:15772300]

233Verrey F et al. (2004) CATs and HATs: the SLC7 family of amino acid transporters. Pflugers Arch. 447: 532‐42 [PMID:14770310]

234Together with the SLC26 family, the SLC4 family of transporters subserve anion exchange, principally of chloride and bicarbonate (HCO 3‐), but also carbonate and hydrogen sulphate (HSO4 ‐). SLC4 family members regulate bicarbonate fluxes as part of carbon dioxide movement, chyme neutralization and reabsorption in the kidney.

235Within 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 suggests a dimeric or tetrameric arrangement, with subunits made up of 13 TM domains and re‐entrant loops at TM9/10 and TM11/12. The N terminus exhibits sites for interaction with multiple proteins, including glycolytic enzymes, haemoglobin and cytoskeletal elements.

236Reithmeier RA et al. (2016) Band 3, the human red cell chloride/bicarbonate anion exchanger (AE1, SLC4A1), in a structural context. Biochim Biophys Acta 1858: 1507‐32 [PMID:27058983]

237The SLC5 family of sodium‐dependent glucose transporters includes, in mammals, the Na+/substrate co‐transporters for glucose (e.g. choline), D‐glucose, monocarboxylates, myo‐inositol and I‐[175, 195, 573, 574]. Members of the SLC5 and SLC6 families, along with other unrelated Na+ cotransporters (i.e. Mhp1 and BetP), share a common structural core that contains an inverted repeat of 5TM α‐helical domains [2].

238Detailed characterisation of members of the hexose transporter family is limited to SGLT1, 2 and 3, which are all inhibited in a competitive manner by phlorizin, a natural dihydrocholine glucoside, that exhibits modest selectivity towards SGLT2 (see [573] for an extensive review). SGLT1 is predominantly 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 [132].

239Recognition 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 [573] 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 [258]. Selective blockers of SGLT2, and thus blocking ˜ 50% of renal glucose reabsorption, are in development for the treatment of diabetes (e.g. [84]).

240The high affinity, hemicholinium‐3‐sensitive, choline transporter (CHT) is expressed mainly in cholinergic neurones on nerve cell terminals and synaptic vesicles (keratinocytes being an additional location). In autonomic neurones, expression of CHT requires an activity‐dependent retrograde signal from postsynaptic neurones [322]. Through recapture of choline generated by the hydrolysis of ACh by acetylcholinesterase, CHT serves to maintain acetylcholine synthesis within the presynaptic terminal [175]. Homozygous mice engineered to lack CHT die within one hour of birth as a result of hypoxia arising from failure of transmission at the neuromuscular junction of the skeletal muscles that support respiration [174]. A low affinity choline uptake mechanism that remains to be identified at the molecular level may involve multiple transporters. In addition, a family of choline transporter‐like (CTL) proteins, (which are members of the SLC44 family) with weak Na+ dependence have been described [528].

241Kiand KD values for hemicholinium‐3 listed in the table are for human CHT expressed in Xenopus laevis oocytes [411], or COS‐7 cells [17]. Hemicholinium mustard is a substrate for CHT that causes covalent modification and irreversible inactivation of the transporter. Several exogenous substances (e.g. triethylcholine) that are substrates for CHT act as precursors to cholinergic false transmitters.

242The sodium‐iodide symporter (NIS) is an iodide transporter found principally in the thyroid gland where it mediates the accumulation of I‐ within thyrocytes. Transport of I‐ by NIS from the blood across the basolateral membrane followed by apical efflux into the colloidal lumen, mediated at least in part by pendrin (SLC22A4), and most likely not SMCT1 (SLC5A8) as once thought, provides the I‐ required for the synthesis of the thyroid hormones triiodothyronine (triiodothyronine) and thyroxine (T4) [49]. NIS is also expressed in the salivary glands, gastric mucosa, intestinal enterocytes and lactating breast. NIS mediates I‐ absorption in the intestine and I‐ secretion into the milk. SMVT is expressed on the apical membrane of intestinal enterocytes and colonocytes and is the main system responsible for biotin(vitamin H) and pantothenic acid (vitamin B5) uptake in humans [463]. SMVT located in kidney proximal tubule epithelial cells mediates the reabsorption of biotin and pantothenic acid. SMCT1 (SLC5A8), which transports a wide range of monocarboxylates, is expressed in the apical membrane of epithelia of the small intestine, colon, kidney, brain neurones and the retinal pigment epithelium [195]. SMCT2 (SLC5A12) also localises to the apical membrane of kidney, intestine, and colon, but in the brain and retina is restricted to astrocytes and Müller cells, respectively [195]. SMCT1 is a high‐affinity transporter whereas SMCT2 is a low‐affinity transporter. The physiological substrates for SMCT1 and SMCT2 are lactate (L‐lactic acid and D‐lactic acid), pyruvic acid, propanoic acid, and nicotinic acid in non‐colonic tissues such as the kidney. SMCT1 is also likely to be the principal transporter for the absorption of nicotinic acid (vitamin B3) in the intestine and kidney [214]. 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 [388]. In the kidney, SMCT2 is responsible for the bulk absorption of lactate because of its low‐affinity/high‐capacity nature. Absence of both transporters in the kidney leads to massive excretion of lactate in urine and consequently drastic decrease in the circulating levels of lactate in blood [521]. SMCT1 also functions as a tumour suppressor in the colon as well as in various other non‐colonic tissues [196]. The tumour‐suppressive function of SMCT1 is based on its ability to transport pyruvic acid, an inhibitor of histone deacetylases, into cells in non‐colonic tissues [522]; in the colon, the ability of SMCT1 to transport butyric acid and propanoic acid, also inhibitors of histone deacetylases, underlies the tumour‐suppressive function of this transporter [195, 196, 233]. The ability of SMCT1 to promote histone acetylase inhibition through accumulation of butyric acid and propanoic acid in immune cells is also responsible for suppression of dendritic cell development in the colon [495].

243I‐, ClO4‐, thiocyanate and NO3 ‐ are competitive substrate inhibitors of NIS [141]. Lipoic acid appears to act as a competitive substrate inhibitor of SMVT [558] and the anticonvulsant drugs primidone and carbamazepine competitively block the transport of biotin by brush border vesicles prepared from human intestine [464].

244Three different mammalian myo‐inositol cotransporters are currently known; two are the Na+‐coupled SMIT1 and SMIT2 tabulated below and the third is proton‐coupled HMIT (SLC2A13). SMIT1 and SMIT2 have a widespread and overlapping tissue location but in polarized cells, such as the Madin‐Darby canine kidney cell line, they segregate to the basolateral and apical membranes, respectively [48]. In the nephron, SMIT1 mediates myo‐inositol uptake as a ‘compatible osmolyte’ when inner medullary tubules are exposed to increases in extracellular osmolality, whilst SMIT2 mediates the reabsorption of myo‐inositol from the filtrate. In some species (e.g. rat, but not rabbit) apically located SMIT2 is responsible for the uptake of myo‐inositol from the intestinal lumen [16].

245The data tabulated are those for dog SMIT1 and rabbit SMIT2. SMIT2 transports D‐chiro‐inositol, but SMIT1 does not. In addition, whereas SMIT1 transports both D‐xylose and L‐xylose and D‐fucose and L‐fucose, SMIT2 transports only the D‐isomers of these sugars [104, 235]. Thus the substrate specificities of SMIT1 (for L‐fucose) and SMIT2 (for D‐chiro‐inositol) allow discrimination between the two SMITs. Human SMIT2 appears not to transport glucose [350].

246DeFronzo RA et al. (2017) Renal, metabolic and cardiovascular considerations of SGLT2 inhibition. Nat Rev Nephrol 13: 11‐26 [PMID:27941935]

247Koepsell H. (2017) The Na+‐D‐glucose cotransporters SGLT1 and SGLT2 are targets for the treatment of diabetes and cancer. Pharmacol Ther 170 148‐165 [PMID:27773781]

248Lehmann A et al. (2016) Intestinal SGLT1 in metabolic health and disease. Am J Physiol Gastrointest Liver Physiol 310 G887‐98 [PMID:27012770]

249Wright EM. (2013) Glucose transport families SLC5 and SLC50. Mol. Aspects Med. 34: 183‐96 [PMID:23506865]

250Wright EM et al. (2011) Biology of human sodium glucose transporters. Physiol. Rev. 91: 733‐94 [PMID:21527736]

251Members of the solute carrier family 6 (SLC6) of sodium‐ and (sometimes chloride‐) dependent neurotransmitter transporters [68, 89, 323] 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 [465]. The members of this superfamily share a structural motif of 10 TM segments that has been observed in crystal structures of the NSS bacterial homolog LeuTAa, a Na+‐dependent amino acid transporter from Aquiflex aeolicus [583] and in several other transporter families structurally related to LeuT [183].

252Monoamine neurotransmission is limited by perisynaptic transporters. Presynaptic monoamine transporters allow recycling of synaptically released noradrenaline, dopamine and 5‐hydroxytry‐ ptamine.

253[125I]RTI55 labels all three monoamine transporters (NET, DAT and SERT) with affinities between 0.5 and 5 nM. Cocaine is an inhibitor of all three transporters with pKi values between 6.5 and 7.2. Potential alternative splicing sites in non‐coding regions of SERT and NET have been identified. A bacterial homologue of SERT shows allosteric modulation by selected anti‐depressants [496].

254The activity of GABA‐transporters located predominantly upon neurones (GAT‐1), glia (GAT‐3) or both (GAT‐2, BGT‐1) serves to terminate phasic GABA‐ergic transmission, maintain low ambient extracellular concentrations of GABA, and recycle GABA for reuse by neurones. Nonetheless, ambient concentrations of GABA are sufficient to sustain tonic inhibition mediated by high affinity GABAA receptors in certain neuronal populations [484]. GAT1 is the predominant GABA transporter in the brain and occurs primarily upon the terminals of presynaptic neurones and to a much lesser extent upon distal astocytic processes that are in proximity to axons terminals. GAT3 resides predominantly on distal astrocytic terminals that are close to the GABAergic synapse. By contrast, BGT1 occupies an extrasynaptic location possibly along with GAT2 which has limited expression in the brain [364]. TauT is a high affinity taurine transporter involved in osmotic balance that occurs in the brain and non‐neuronal tissues, such as the kidney, brush border membrane of the intestine and blood brain barrier [89, 241]. CT1, which transports creatine, has a ubiquitous expression pattern, often co‐localizing with creatine kinase [89].

255The IC50 values for GAT1‐4 reported in the table reflect the range reported in the literature from studies of both human and mouse transporters. There is a tendency towards lower IC50 values for the human orthologue [327]. SNAP‐5114 is only weakly selective for GAT 2 and GAT3, with IC50 values in the range 22 to >30 μM at GAT1 and BGT1, whereas NNC052090 has at least an order of magnitude selectivity for BGT1 [see [107, 480] for reviews]. Compound (R)‐4d is a recently described compound that displays 20‐fold selectivity for GAT3 over GAT1 [190]. In addition to the inhibitors listed, deramciclane is a moderately potent, though non‐selective, inhibitor of all cloned GABA transporters (IC50 = 26‐46 μM; [127]). Diaryloxime and diarylvinyl ether derivatives of nipecotic acid and guvacine that potently inhibit the uptake of [3H]GABA into rat synaptosomes have been described [309]. Several derivatives of exo‐THPO(e.g. N‐methyl‐exo‐THPO and N‐acetyloxyethyl‐exo‐THPO) demonstrate selectivity as blockers of astroglial, versus neuronal, uptake of GABA[see [102, 479] for reviews]. GAT3 is inhibited by physiologically relevant concentrations of Zn2+[106]. Taut transports GABA, but with low affinity, but CT1 does not, although it can be engineered to do so by mutagenesis guided by LeuT as a structural template [133]. Although inhibitors of creatine transport by CT1 (e.g. β‐guanidinopropionic acid, cyclocreatine, guanidinoethane sulfonic acid) are known (e.g. [114]) they insufficiently characterized to be included in the table.

256Two gene products, GlyT1 and GlyT2, are known that give rise to transporters that are predominantly located on glia and neurones, respectively. Five variants of GlyT1 (a,b,c,d & e) differing in their N‐ and C‐termini are generated by alternative promoter usage and splicing, and three splice variants of GlyT2 (a,b & c) have also been identified (see [42, 165, 211, 504] for reviews). GlyT1 transporter isoforms expressed in glia surrounding glutamatergic synapses regulate synaptic glycine concentrations influencing NMDA receptor‐mediated neurotransmission [41, 191], but also are important, in early neonatal life, for regulating glycine concentrations at inhibitory glycinergic synapses [212]. 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 [212, 530]. Disruption of GlyT1 restricted to forebrain neurones is associated with enhancement of EPSCs mediated by NMDA receptors and behaviours that are suggestive of a promnesic action [588]. GlyT2 transporters localised on the axons and boutons of glycinergic neurones appear crucial for efficient transmitter loading of synaptic vesicles but may not be essential for the termination of inhibitory neurotransmission [213, 457]. Mice in which GlyT2 has been deleted develop a fatal hyperekplexia phenotype during the second postnatal week [213] and mutations in the human gene encoding GlyT2 (SLC6A5) have been identified in patients with hyperekplexia (reviewed by [243]). ATB0+(SLC6A14) is a transporter for numerous dipolar and cationic amino acids and thus has a much broader substrate specificity than the glycine transporters alongside which it is grouped on the basis of structural similarity [89]. ATB0+ is expressed in various peripheral tissues [89]. By contrast PROT (SLC6A7), which is expressed only in brain in association with a subset of excitatory nerve terminals, shows specificity for the transport of L‐proline.

257sarcosine is a selective transportable inhibitor of GlyT1 and also a weak agonist at the glycine binding site of the NMDA receptor [601], but has no effect on GlyT2. This difference has been attributed to a single glycine residue in TM6 (serine residue in GlyT2) [546]. Inhibition of GLYT1 by the sarcosine derivatives NFPS, NPTS and Org 24598 is non‐competitive [366, 366]. IC50 values for Org 24598 reported in the literature vary, most likely due to differences in assay conditions [62, 366]. The tricyclic antidepressant amoxapine weakly inhibits GlyT2 (IC50 92 μM) with approximately 10‐fold selectivity over GlyT1 [406]. The endogenous lipids arachidonic acid and anandamide exert opposing effects upon GlyT1a, inhibiting (IC50 ˜ 2 μM) and potentiating (EC50 ˜ 13 μM) transport currents, respectively [421]. 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 [148, 280, 567]. Protons [25] and Zn2+[284] act as non‐competitive inhibitors of GlyT1b, with IC50 values of ˜ 100 nM and ˜ 10 μM respectively, but neither ion affects GlyT2 (reviewed by [544]). Glycine transport by GLYT1 is inhibited by Li+, whereas GLYT2 transport is stimulated (both in the presence of Na+) [433].

258Certain members of neutral amino acid transport family are expressed upon the apical surface of epithelial cells and are important for the absorption of amino acids from the duodenum, jejunum and ileum and their reabsorption within the proximal tubule of the nephron (i.e. B0AT1 (SLC6A19), SLC6A17, SLC6A18, SLC6A20). Others may function as transporters for neurotransmitters or their precursors (i.e. B0AT2, SLC6A17) [69].

259Bermingham, DP et al. (2016) Kinase‐dependent Regulation of Monoamine Neurotransmitter Transporters. Pharmacol Rev 68: 888‐953 [PMID:27591044]

260Bröer S et al. (2012) The solute carrier 6 family of transporters. Br. J. Pharmacol. 167: 256‐78 [PMID:22519513]

261Joncquel‐Chevalier Curt M et al. (2015) Creatine biosynthesis and transport in health and disease. Biochimie 119: 146‐65 [PMID:26542286]

262Lohr KM et al. (2017) TMembrane transporters as mediators of synaptic dopamine dynamics: implications for disease. Eur J Neurosci 45: 20‐33 [PMID:27520881]

263Pramod AB et al. (2013) SLC6 transporters: structure, function, regulation, disease association and therapeutics. Mol. Aspects Med. 34: 197‐219 [PMID:23506866]

264The sodium/calcium exchangers (NCX) use the extracellular sodium concentration to facilitate the extrusion of calcium out of the cell. Alongside the plasma membrane Ca2+‐ATPase (PMCA) and sarcoplasmic/endoplasmic reticulum Ca2+‐ATPase (SERCA), as well as the sodium/potassium/calcium exchangers (NKCX, SLC24 family), NCX allow recovery of intracellular calcium back to basal levels after cellular stimulation. When intracellular sodium ion levels rise, for example, following depolarisation, these transporters can operate in the reverse direction to allow calcium influx and sodium efflux, as an electrogenic mechanism. Structural modelling suggests the presence of 9 TM segments, with a large intracellular loop between the fifth and sixth TM segments.

265Although subtype‐selective inhibitors of NCX function are not widely available, 3,4‐dichlorobenzamil and CBDMB act as non‐selective NCX inhibitors, while SEA0400, KB‐R7943, SN6, and ORM‐10103[283] act to inhibit NCX function with varying degrees of selectivity. BED is a selective NCX3 inhibitor [481] and and YM‐244769 inhibits NCX3 preferentially over other isoforms [277].

266Khananshvili D. (2013) The SLC8 gene family of sodium‐calcium exchangers (NCX) ‐ structure, function, and regulation in health and disease. Mol Aspects Med 34: 220‐35 [PMID:23506867]

267Sekler I (2015) Standing of giants shoulders the story of the mitochondrial Na(+)Ca(2+) exchanger. Biochem Biophys Res Commun 460: 50‐2 [PMID:25998733]

268Sodium/hydrogen exchangers or sodium/proton antiports are a family of transporters that maintain cellular pH by utilising the sodium gradient across the plasma membrane to extrude protons produced by metabolism, in a stoichiometry of 1 Na+ (in): 1 H+(out). Several isoforms, NHE6, NHE7, NHE8 and NHE9 appear to locate on intracellular membranes [389, 397, 405]. Li+ and NH4 +, but not K+, ions may also be transported by some isoforms. Modelling of the topology of these transporters indicates 12 TM regions with an extended intracellular C‐terminus containing multiple regulatory sites.

269NHE1 is considered to be a ubiquitously‐expressed ‘housekeeping’ transporter. NHE3 is highly expressed in the intestine and kidneys and regulate sodium movements in those tissues. NHE10 is present in sperm [557] and osteoclasts [338]; gene disruption results in infertile male mice [557].

270Information on members of this family may be found in the online database.

271Analogues 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 [110, 531, 532].

272Donowitz M et al. (2013) SLC9/NHE gene family, a plasma membrane and organellar family of Na+/H+ exchangers. Mol. Aspects Med. 34: 236‐51 [PMID:23506868]

273Kato A et al. (2011) Regulation of electroneutral NaCl absorption by the small intestine. Annu. Rev. Physiol. 73: 261‐81 [PMID:21054167]

274Ohgaki R et al. (2011) Organellar Na+/H+ exchangers: novel players in organelle pH regulation and their emerging functions. Biochemistry 50: 443‐50 [PMID:21171650]

275Parker MD et al. (2015) Na+‐H+ exchanger‐1 (NHE1) regulation in kidney proximal tubule. Cell. Mol. Life Sci. 72: 2061‐74 [PMID:25680790]

276Ruffin VA et al. (2014) Intracellular pH regulation by acid‐base transporters in mammalian neurons. Front Physiol 5: 43 [PMID:24592239]

277The 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 [119, 308]. SLC10A6 (SOAT) functions as a sodium‐dependent transporter of sulphated solutes including sulfphated steroids and bile acids [205, 207]. Transport function has not yet been demonstrated for the 4 remaining members of the SLC10 family, SLC10A3 (P3), SLC10A4 (P4), SLC10A5 (P5), and SLC10A7 (P7), and the identity of their endogenous substrates remain unknown [176, 207, 210, 553]. Members of the SLC10 family are predicted to have seven transmembrane domains with an extracellular N‐terminus and cytoplasmic C‐terminus [35, 236].

278Heterologously expressed SLC10A4 [206] or SLC10A7 [210] failed to exhibit significant transport of taurocholic acid, pregnenolone sulphate, dehydroepiandrosterone sulphate or choline. SLC10A4 has recently been suggested to associate with neuronal vesicles [72].

279Anwer MS et al. (2014) Sodium‐dependent bile salt transporters of the SLC10A transporter family: more than solute transporters. Pflugers Arch. 466: 77‐89 [PMID:24196564]

280Claro da Silva T et al. (2013) The solute carrier family 10 (SLC10): beyond bile acid transport. Mol. Aspects Med. 34: 252‐69 [PMID:23506869]

281Dawson PA et al. (2017) Roles of Ileal ASBT and OSTalpha‐OSTbeta in Regulating Bile. Dig Dis 35: 261‐266 [PMID:28249269]

282Zwicker BL et al. (2013) Transport and biological activities of bile acids. Int. J. Biochem. Cell Biol. 45: 1389‐98 [PMID:23603607]

283The family of proton‐coupled metal ion transporters are responsible for movements of divalent cations, particularly ferrous and manganese ions, across the cell membrane (SLC11A2/DMT1) and across endosomal (SLC11A2/DMT1) or lysosomal/phagosomal membranes (SLC11A1/NRAMP1), dependent on proton transport. Both proteins appear to have 12 TM regions and cytoplasmic N‐ and C‐ termini. NRAMP1 is involved in antimicrobial action in macrophages, although its precise mechanism is undefined. Facilitated diffusion of divalent cations into phagosomes may increase intravesicular free radicals to damage the pathogen. Alternatively, export of divalent cations from the phagosome may deprive the pathogen of essential enzyme cofactors. SLC11A2/DMT1 is more widely expressed and appears to assist in divalent cation assimilation from the diet, as well as in phagocytotic cells.

284Loss‐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).

285Codazzi F et al. (2015) Iron entry in neurons and astrocytes: a link with synaptic activity. Front Mol Neurosci 8: 18 [PMID:26089776]

286Montalbetti N et al. (2013) Mammalian iron transporters: families SLC11 and SLC40. Mol. Aspects Med. 34: 270‐87 [PMID:23506870]

287Wessling‐Resnick M. (2015) Nramp1 and Other Transporters Involved in Metal Withholding during Infection. J. Biol. Chem. 290: 18984‐90 [PMID:26055722]

288Zheng W et al. (2012) Regulation of brain iron and copper homeostasis by brain barrier systems: implication in neurodegenerative diseases. Pharmacol. Ther. 133: 177‐88 [PMID:22115751]

289The SLC12 family of chloride transporters contribute to ion fluxes across a variety of tissues, particularly in the kidney and choroid plexus of the brain. Within this family, further subfamilies are identifiable: NKCC1, NKCC2 and NCC constitute a group of therapeutically‐relevant transporters, targets for loop and thiazide diuretics. These 12 TM proteins exhibit cytoplasmic termini and an extended extracellular loop at TM7/8 and are kidney‐specific (NKCC2 and NCC) or show a more widespread distribution (NKCC1). A second family, the K‐Cl co‐transporters are also 12 TM domain proteins with cytoplasmic termini, but with an extended extracellular loop at TM 5/6. CCC6 exhibits structural similarities with the K‐Cl co‐transporters, while CCC9 is divergent, with 11 TM domains and a cytoplasmic N‐terminus and extracellular C‐terminus.

290DIOA is able to differentiate KCC isoforms from NKCC and NCC transporters, but also inhibits CFTR [275].

291Arroyo JP et al. (2013) The SLC12 family of electroneutral cation‐coupled chloride cotransporters. Mol. Aspects Med. 34: 288‐98 [PMID:23506871]

292Bachmann S et al. (2017) Regulation of renal Na‐(K)‐Cl cotransporters by vasopressin. Pflugers Arch [PMID:28577072]

293Bazua‐Valenti S et al. (2016) Physiological role of SLC12 family members in the kidney. Am J Physiol Renal Physiol 311 F131‐44 [PMID:27097893]

294Huang X et al. (2016) Everything we always wanted to know about furosemide but were afraid to ask. Am J Physiol Renal Physiol 310: F958‐71 [PMID:26911852]

295Kahle KT et al. (2015) K‐Cl cotransporters, cell volume homeostasis, and neurological disease. Trends Mol Med [PMID:26142773]

296Martin‐Aragon Baudel MA et al. (2017) Chloride co‐transporters as possible therapeutic targets for stroke. J Neurochem 140: 195‐209 [PMID:27861901]

297Within 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.

298Bergeron MJ et al. (2013) SLC13 family of Na(+)‐coupled di‐ and tri‐carboxylate/sulfate transporters. Mol Aspects Med 34: 299‐312 [PMID:23506872]

299Markovich D. (2014) Na+‐sulfate cotransporter SLC13A1. Pflugers Arch. 466: 131‐7 [PMID:24193406]

300Pajor AM. (2014) Sodium‐coupled dicarboxylate and citrate transporters from the SLC13 family. Pflugers Arch. 466: 119‐30 [PMID:24114175]

301As 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 [500]. Topographical modelling suggests that the majority of the variants of SLC14 transporters have 10 TM domains, with a glycosylated extracellular loop at TM5/6, and intracellular C‐ and N‐termini. The UT‐A1 splice variant, exceptionally, has 20 TM domains, equivalent to a combination of the UT‐A2 and UT‐A3 splice variants.

302Esteva‐Font C et al. (2015) Urea transporter proteins as targets for small‐molecule diuretics. Nat Rev Nephrol 11: 113‐23 [PMID:25488859]

303LeMoine CM et al. (2015) Evolution of urea transporters in vertebrates: adaptation to urea's multiple roles and metabolic sources. J. Exp. Biol. 218: 1936‐1945 [PMID:26085670]

304Pannabecker TL. (2013) Comparative physiology and architecture associated with the mammalian urine concentrating mechanism: role of inner medullary water and urea transport pathways in the rodent medulla. Am. J. Physiol. Regul. Integr. Comp. Physiol. 304: R488‐503 [PMID:23364530]

305Shayakul C et al. (2013) The urea transporter family (SLC14): physiological, pathological and structural aspects. Mol. Aspects Med. 34: 313‐22 [PMID:23506873]

306Stewart G. (2011) The emerging physiological roles of the SLC14A family of urea transporters. Br. J. Pharmacol. 164: 1780‐92 [PMID:21449978]

307The 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 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.

308The members of the SLC15 family of peptide transporters are particularly promiscuous in the transport of di/tripeptides, and D‐amino acid containing peptides are also transported. While SLC15A3 and SLC15A4 transport histidine, none of them transport tetrapeptides. In addition, many molecules, among which beta‐lactam antibiotics, angiotensin‐converting enzyme inhibitors and sartans, variably interact with the SLC15 family transporters. Known substrates include cefadroxil, valacyclovir, 5‐aminolevulinic acid, L‐Dopa prodrugs, gemcitabine prodrugs, floxuridine prodrugs, Maillard reaction products, JBP485, zanamivir and oseltamivir prodrugs, and didanosine prodrugs.

309There is evidence to suggest the existence of a fifth member of this transporter family, SLC15A5(A6NIM6; ENSG00000188991), but to date there is no established biological function or reported pharmacology for this protein [498].

310Smith DE et al. (2013) Proton‐coupled oligopeptide transporter family SLC15: physiological, pharmacological and pathological implications. Mol. Aspects Med. 34: 323‐36 [PMID:23506874]

311Members 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.

312The 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.

313MCT1 and MCT2, but not MCT3 and MCT4, are inhibited by CHC, which also inhibits members of the mitochondrial transporter family, SLC25.

314MCT5‐MCT7, MCT9 and MCT11‐14 are regarded as orphan transporters.

315Bernal J et al. (2015) Thyroid hormone transporters‐functions and clinical implications. Nat Rev Endocrinol 11: 406‐417 [PMID:25942657]

316Jones RS. (2016) Monocarboxylate Transporters: Therapeutic Targets and Prognostic Factors in Disease. Clin Pharmacol Ther 100: 454‐463 [PMID:27351344]

317Halestrap AP. (2013) The SLC16 gene family ‐ structure, role and regulation in health and disease. Mol Aspects Med 34: 337‐49 [PMID:23506875]

318The 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.

319Type I sodium‐phosphate co‐transporters are expressed in the kidney and intestine.

320The sialic acid transporter is expressed on both lysosomes and synaptic vesicles, where it appears to allow export of sialic acid and accumulation of acidic amino acids, respectively [387], driven by proton gradients. In lysosomes, degradation of glycoproteins generates amino acids and sugar residues, which are metabolized further following export from the lysosome.

321Loss‐of‐function mutations in sialin are associated with Salla disease (OMIM: 604369), an autosomal recessive neurodegenerative disorder associated with sialic acid storage disease [551].

322Vesicular glutamate transporters (VGLUTs) allow accumulation of glutamate into synaptic vesicles, as well as secretory vesicles in endocrine tissues. The roles of VGLUTs in kidney and liver are unclear. These transporters appear to utilize the proton gradient and also express a chloride conductance [39].

323Endogenous ketoacids produced during fasting have been proposed to regulate VGLUT function through blocking chloride ion‐mediated allosteric enhancement of transporter function [285].

324The vesicular nucleotide transporter is the most recent member of the SLC17 family to have an assigned function. Uptake of ATP was independent of pH, but dependent on chloride ions and membrane potential [473].

325VGLUTs and VNUT can be inhibited by DIDS and evans blue dye.

326Moriyama Y et al. (2017) Vesicular nucleotide transporter (VNUT): appearance of an actress on the stage of purinergic signaling. Purinergic Signal [PMID:28616712]

327Omote H et al. (2016) Structure, Function, and Drug Interactions of Neurotransmitter Transporters in the Postgenomic Era. Annu Rev Pharmacol Toxicol 56: 385‐402 [PMID:26514205]

328Reimer RJ. (2013) SLC17: a functionally diverse family of organic anion transporters. Mol. Aspects Med. 34: 350‐9 [PMID:23506876]

329Takamori S. (2016) Vesicular glutamate transporters as anion channels? Pflugers Arch 468 513‐8 [PMID:26577586]

330The vesicular amine transporters (VATs) are putative 12 TM domain proteins that function to transport singly positively charged amine neurotransmitters and hormones from the cytoplasm and concentrate them within secretory vesicles. They function as amine/proton antiporters driven by secondary active transport utilizing the proton gradient established by a multi‐subunit vacuolar ATPase that acidifies secretory vesicles (reviewed by [151]). The vesicular acetylcholine transporter (VAChT; [160]) localizes to cholinergic neurons, but non‐neuronal expression has also been claimed [476]. Vesicular monoamine transporter 1 (VMAT1, [158]) is mainly expressed in peripheral neuroendocrine cells, but most likely not in the CNS, whereas VMAT2 [159] distributes between both central and peripheral sympathetic monoaminergic neurones [152]. The vescular polyamine transporter (VPAT) is highly expressed in the lungs and placenta, with moderate expression in brain and testis, and with low expression in heart and skeletal muscle [250]. VPAT mediates vesicular accumulation of polyamines in mast cells [510].

331pKi values for endogenous and synthetic substrate inhibitors of human VMAT1 and VMAT2 are for inhibition of [3H]5‐HT uptake in transfected and permeabilised CV‐1 cells as detailed by [159]. In addition to the monoamines listed in the table, the trace amines tyramine and β‐phenylethylamine are probable substrates for VMAT2 [152]. Probes listed in the table are those currently employed; additional agents have been synthesized (e.g. [611]).

332German CL et al. (2015) Regulation of the Dopamine and Vesicular Monoamine Transporters: Pharmacological Targets and Implications for Disease. Pharmacol Rev 67: 1005‐24 [PMID:26408528]

333Lawal HO et al. (2013) SLC18: Vesicular neurotransmitter transporters for monoamines and acetylcholine. Mol. Aspects Med. 34: 360‐72 [PMID:23506877]

334Lohr KM et al. (2017) Membrane transporters as mediators of synaptic dopamine dynamics: implications for disease. Eur J Neurosci 45: 20‐33 [PMID:27520881]

335Omote H et al. (2016) Structure, Function, and Drug Interactions of Neurotransmitter Transporters in the Postgenomic Era. Annu Rev Pharmacol Toxicol 56: 385‐402 [PMID:26514205]

336Sitte HH et al. (2015) Amphetamines, new psychoactive drugs and the monoamine transporter cycle. Trends Pharmacol Sci 36: 41‐50 [PMID:25542076]

337Wimalasena K. (2011) Vesicular monoamine transporters: structure‐function, pharmacology, and medicinal chemistry. Med Res Rev 31: 483‐519 [PMID:20135628]

338The 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.

339Loss‐of‐function mutations in ThTr1 underlie thiamine‐responsive megaloblastic anemia syndrome [130].

340Matherly LH et al. (2014) The major facilitative folate transporters solute carrier 19A1 and solute carrier 46A1: biology and role in antifolate chemotherapy of cancer. Drug Metab. Dispos. 42: 632‐49 [PMID:24396145]

341Zhao R et al. (2013) Folate and thiamine transporters mediated by facilitative carriers (SLC19A1‐3 and SLC46A1) and folate receptors. Mol. Aspects Med. 34: 373‐85 [PMID:23506878]

342The 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.

343Biber J et al. (2013) Phosphate transporters and their function. Annu. Rev. Physiol. 75: 535‐50 [PMID:23398154]

344Forster IC et al. (2013) Phosphate transporters of the SLC20 and SLC34 families. Mol. Aspects Med. 34: 386‐95 [PMID:23506879]

345Shobeiri N et al. (2013) Phosphate: an old bone molecule but new cardiovascular risk factor. Br J Clin Pharmacol [PMID:23506202]

346The 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.

347Organic cation transporters (OCT) are electrogenic, Na+‐independent and reversible.

348corticosterone and quinine are able to inhibit all three organic cation transporters.

349A‐González N et al. (2011) Liver X receptors as regulators of macrophage inflammatory and metabolic pathways. Biochim. Biophys. Acta 1812: 982‐94 [PMID:21193033]

350Koepsell H. (2013) The SLC22 family with transporters of organic cations, anions and zwitterions. Mol. Aspects Med. 34: 413‐35 [PMID:23506881]

351Lozano E et al. (2013) Role of the plasma membrane transporter of organic cations OCT1 and its genetic variants in modern liver pharmacology. Biomed Res Int 2013: 692071 [PMID:23984399]

352Pelis RM et al. (2014) SLC22, SLC44, and SLC47 transporters–organic anion and cation transporters: molecular and cellular properties. Curr Top Membr 73: 233‐61 [PMID:24745985]

353Yin J et al. (2016) Renal drug transporters and their significance in drug‐drug interactions. Acta Pharm Sin B 6: 363‐373 [PMID:27709005]

354Organic zwitterions/cation transporters (OCTN) function as organic cation uniporters, organic cation/proton exchangers or sodium/L‐carnitine co‐transporters.

355Pochini L et al. (2013) OCTN cation transporters in health and disease: role as drug targets and assay development. J Biomol Screen 18: 851‐67 [PMID:23771822]

356Tamai I. (2013) Pharmacological and pathophysiological roles of carnitine/organic cation transporters (OCTNs: SLC22A4, SLC22A5 and Slc22a21). Biopharm Drug Dispos 34: 29‐44 [PMID:22952014]

357Yin J et al. (2016) Renal drug transporters and their significance in drug‐drug interactions. Acta Pharm Sin B 6: 363‐373 [PMID:27709005]

358Organic anion transporters (OATs) are non‐selective transporters prominent in the kidney and intestine

359Koepsell H. (2013) The SLC22 family with transporters of organic cations, anions and zwitterions. Mol. Aspects Med. 34: 413‐35 [PMID:23506881]

360Yin J et al. (2016) Renal drug transporters and their significance in drug‐drug interactions. Acta Pharm Sin B 6: 363‐373 [PMID:27709005]

361Burckhardt G. (2012) Drug transport by Organic Anion Transporters (OATs). Pharmacol. Ther. 136: 106‐30 [PMID:22841915]

362Koepsell H. (2013) The SLC22 family with transporters of organic cations, anions and zwitterions. Mol. Aspects Med. 34: 413‐35 [PMID:23506881]

363König J et al. (2013) Transporters and drug‐drug interactions: important determinants of drug disposition and effects. Pharmacol. Rev. 65: 944‐66 [PMID:23686349]

364Motohashi H et al. (2013) Organic cation transporter OCTs (SLC22) and MATEs (SLC47) in the human kidney. AAPS J 15: 581‐8 [PMID:23435786]

365Predicted 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.

366Bürzle M et al. (2013) The sodium‐dependent ascorbic acid transporter family SLC23. Mol. Aspects Med. 34: 436‐54 [PMID:23506882]

367May JM. (2011) The SLC23 family of ascorbate transporters: ensuring that you get and keep your daily dose of vitamin C. Br. J. Pharmacol. 164: 1793‐801 [PMID:21418192]

368The sodium/potassium/calcium exchange family of transporters utilize the extracellular sodium gradient to drive calcium and potassium co‐transport out of the cell. As is the case for NCX transporters (SLC8A family), NKCX transporters are thought to be bidirectional, with the possibility of calcium influx following depolarization of the plasma membrane. Topological modeling suggests the presence of 10 TM domains, with a large intracellular loop between the fifth and sixth TM regions.

369NKCX6 has been proposed to be the sole member of a CAX Na+/Ca2+ exchanger family, which may be the mitochondrial transporter responsible for calcium accumulation from the cytosol [483].

370Schnetkamp PP. (2013) The SLC24 gene family of Na+/Ca2 +‐K+ exchangers: from sight and smell to memory consolidation and skin pigmentation. Mol. Aspects Med. 34: 455‐64 [PMID:23506883]

371Schnetkamp PP et al. (2014) The SLC24 family of K+‐dependent Na+‐Ca2 + exchangers: structure‐function relationships. Curr Top Membr 73: 263‐87 [PMID:24745986]

372Sekler I. (2015) Standing of giants shoulders the story of the mitochondrial Na(+)Ca(2+) exchanger. Biochem. Biophys. Res. Commun. 460: 50‐2 [PMID:25998733]

373Mitochondrial transporters are nuclear‐encoded proteins, which convey solutes across the inner mitochondrial membrane. Topological modelling suggests homodimeric transporters, each with six TM segments and termini in the cytosol.

374Mitochondrial 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.

375Mitochondrial amino acid transporters can be subdivided on the basis of their substrates. Mitochondrial ornithine transporters play a role in the urea cycle by exchanging cytosolic ornithine (L‐ornithine and D‐ornithine) for mitochondrial citrulline (L‐citrulline and D‐citrulline) in equimolar amounts. Further members of the family include transporters of S‐adenosylmethionine and carnitine.

376Both ornithine transporters are inhibited by the polyamine spermine[178]. Loss‐of‐function mutations in these genes are associated with hyperornithinemia‐hyperammonemia‐homocitrulli‐ nuria.

377Mitochondrial phosphate transporters allow the import of inorganic phosphate for ATP production.

378Mitochondrial nucleotide transporters, defined by structural similarlities, include the adenine nucleotide translocator family (SLC25A4, SLC25A5, SLC25A6 and SLC25A31), which under conditions of aerobic metabolism, allow coupling between mitochondrial oxidative phosphorylation and cytosolic energy consumption by exchanging cytosolic ADP for mitochondrial ATP. Further members of the mitochondrial nucleotide transporter subfamily convey diverse substrates including CoA, although not all members have had substrates identified.

379Mitochondrial uncoupling proteins allow dissipation of the mitochondrial proton gradient associated with thermogenesis and regulation of radical formation.

380Many of the transporters identified below have yet to be assigned functions and are currently regarded as orphans.

381Information on members of this family may be found in the online database.

382Baffy G. (2017) Mitochondrial uncoupling in cancer cells: Liabilities and opportunities. Biochim Biophys Acta 1858: 655‐664 [PMID:28088333]

383Bertholet, AM et al. (2017) UCP1: A transporter for H+ and fatty acid anions. Biochimie 134: 28‐34 [PMID:27984203]

384Clémençon B et al. (2013) The mitochondrial ADP/ATP carrier (SLC25 family): pathological implications of its dysfunction. Mol. Aspects Med. 34: 485‐93 [PMID:23506884]

385Palmieri F. (2013) The mitochondrial transporter family SLC25: identification, properties and physiopathology. Mol. Aspects Med. 34: 465‐84 [PMID:23266187]

386Seifert EL et al. (2015) The mitochondrial phosphate carrier: Role in oxidative metabolism, calcium handling and mitochondrial disease. Biochem. Biophys. Res. Commun. 464: 369‐75 [PMID:26091567]

387Taylor, EB. (2017) Functional Properties of the Mitochondrial Carrier System. Trends Cell Biol [PMID:28522206]

388Along 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).

389Alper SL et al. (2013) The SLC26 gene family of anion transporters and channels. Mol. Aspects Med. 34: 494‐515 [PMID:23506885]

390Kato A et al. (2011) Regulation of electroneutral NaCl absorption by the small intestine. Annu. Rev. Physiol. 73: 261‐81 [PMID:21054167]

391Nofziger C et al. (2011) Pendrin function in airway epithelia. Cell. Physiol. Biochem. 28: 571‐8 [PMID:22116372]

392Soleimani M. (2013) SLC26 Cl(‐)/HCO3(‐) exchangers in the kidney: roles in health and disease. Kidney Int. [PMID:23636174]

393Fatty acid transporter proteins (FATPs) are a family (SLC27) of six transporters (FATP1‐6). They have at least one, and possibly six [343, 475], transmembrane segments, and are predicted on the basis of structural similarities to form dimers. SLC27 members have several structural domains: integral membrane associated domain, peripheral membrane associated domain, FATP signature, intracellular AMP binding motif, dimerization domain, lipocalin motif, and an ER localization domain (identified in FATP4 only) [166, 383, 413]. These transporters are unusual in that they appear to express intrinsic very long‐chain acyl‐CoA synthetase (EC 6.2.1.‐, EC 6.2.1.7) enzyme activity. Within the cell, these transporters may associate with plasma and peroxisomal membranes. FATP1‐4 and ‐6 transport long‐ and very long‐chain fatty acids, while FATP5 transports long‐chain fatty acids as well as bile acids [381, 475].

394Although the stoichiometry of fatty acid transport is unclear, it has been proposed to be facilitated by the coupling of fatty acid transport to conjugation with coenzyme A to form fatty acyl CoA esters. Small molecule inhibitors of FATP2 [345, 471] and FATP4 [50, 609], as well as bile acid inhibitors of FATP5 [609], have been described; analysis of the mechanism of action of some of these inhibitors suggests that transport may be selectively inhibited without altering enzymatic activity of the FATP.

395C1‐BODIPY‐C12 accumulation has been used as a non‐selective index of fatty acid transporter activity.

396FATP2 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.

397Anderson CM et al. (2013) SLC27 fatty acid transport proteins. Mol. Aspects Med. 34: 516‐28 [PMID:23506886]

398Dourlen P et al. (2015) Fatty acid transport proteins in disease: New insights from invertebrate models. Prog Lipid Res 60: 30‐40 [PMID:26416577]

399Schwenk RW et al. (2010) Fatty acid transport across the cell membrane: regulation by fatty acid transporters. Prostaglandins Leukot. Essent. Fatty Acids 82: 149‐54 [PMID:20206486]

400Nucleoside 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.

401SLC28 family membersappear to have 13 TM segments with cytoplasmic N‐termini and extracellular C‐termini, and function as concentrative nucleoside transporters.

402A 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).

403SLC29 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 [32]. ENT1‐3 are described as broad‐spectrum equilibrative nucleoside transporters, while ENT4 is primarily a polyspecific organic cation transporter at neutral pH [252]. ENT4 transports adenosine only under acidotic conditions [36].

404Boswell‐Casteel RC et al. (2017) Equilibrative nucleoside transporters‐A review. Nucleosides Nucleotides Nucleic Acids 36: 7‐30 [PMID:27759477]

405Pastor‐Anglada M et al. (2015) Nucleoside transporter proteins as biomarkers of drug responsiveness and drug targets. Front Pharmacol 6: 13 [PMID:25713533]

406Young JD et al. (2013) The human concentrative and equilibrative nucleoside transporter families, SLC28 and SLC29. Mol. Aspects Med. 34: 529‐47 [PMID:23506887]

407Young JD. (2016) The SLC28 (CNT) and SLC29 (ENT) nucleoside transporter families: a 30‐year collaborative odyssey. Biochem Soc Trans 44: 869‐76 [PMID:27284054]

408Along with the SLC39 family, SLC30 transporters regulate the movement of zinc ions around the cell. In particular, these transporters remove zinc ions from the cytosol, allowing accumulation into intracellular compartments or efflux through the plasma membrane. ZnT1 is thought to be placed on the plasma membrane extruding zinc, while ZnT3 is associated with synaptic vesicles and ZnT4 and ZnT5 are linked with secretory granules. Membrane topology predictions suggest a multimeric assembly, potentially heteromultimeric [506], with subunits having six TM domains, and both termini being cytoplasmic. Dityrosine covalent linking has been suggested as a mechanism for dimerisation, particularly for ZnT3 [469]. The mechanism for zinc transport is unknown.

409Information on members of this family may be found in the online database.

410ZnT8/SLC30A8 is described as a type 1 diabetes susceptibility gene.

411Zinc fluxes may be monitored through the use of radioisotopic Zn‐65 or the fluorescent dye FluoZin 3.

412Bouron A et al. (2013) Contribution of calcium‐conducting channels to the transport of zinc ions. Pflugers Arch. [PMID:23719866]

413Hojyo S et al. (2016) Zinc transporters and signaling in physiology and pathogenesis. Arch Biochem Biophys 611: 43‐50 [PMID:27394923]

414Huang L et al. (2013) The SLC30 family of zinc transporters ‐ a review of current understanding of their biological and pathophysiological roles. Mol. Aspects Med. 34: 548‐60 [PMID:23506888]

415Kambe T et al. (2014) Current understanding of ZIP and ZnT zinc transporters in human health and diseases. Cell. Mol. Life Sci. 71: 3281‐95 [PMID:24710731]

416Kambe T et al. (2015) The Physiological, Biochemical, and Molecular Roles of Zinc Transporters in Zinc Homeostasis and Metabolism. Physiol. Rev. 95: 749‐784 [PMID:26084690]

417SLC31 family members, alongside the Cu‐ATPases are involved in the regulation of cellular copper levels. The CTR1 transporter is a cell‐surface transporter to allow monovalent copper accumulation into cells, while CTR2 appears to be a vacuolar/vesicular transporter [442]. Functional copper transporters appear to be trimeric with each subunit having three TM regions and an extracellular N‐terminus. CTR1 is considered to be a higher affinity copper transporter compared to CTR2. The stoichiometry of copper accumulation is unclear, but appears to be energy‐independent [334].

418Copper accumulation through CTR1 is sensitive to silver ions, but not divalent cations [334].

419Howell SB et al. (2010) Copper transporters and the cellular pharmacology of the platinum‐containing cancer drugs. Mol. Pharmacol. 77: 887‐94 [PMID:20159940]

420Kaplan JH et al. (2016) How Mammalian Cells Acquire Copper: An Essential but Potentially Toxic Metal. Biophys J 110: 7‐13 [PMID:26745404]

421Kim H et al. (2013) SLC31 (CTR) family of copper transporters in health and disease. Mol. Aspects Med. 34: 561‐70 [PMID:23506889]

422Monné M et al. (2014) Antiporters of the mitochondrial carrier family. Curr Top Membr 73: 289‐320 [PMID:24745987]

423The vesicular inhibitory amino acid transporter, VIAAT (also termed the vesicular GABA transporter VGAT), which is the sole representative of the SLC32 family, transports GABA, or glycine, into synaptic vesicles [200, 201], and is a member of the structurally‐defined amino acid‐polyamine‐organocation/APC clan composed of SLC32, SLC36 and SLC38 transporter families (see [477]). VIAAT was originally suggested to be composed of 10 TM segments with cytoplasmic N‐ and C‐termini [372]. However, an alternative 9TM structure with the N terminus facing the cytoplasm and the C terminus residing in the synaptic vesicle lumen has subsequently been reported [369]. VIAAT acts as an antiporter for inhibitory amino acids and protons. The accumulation of GABA and glycine within vesicles is driven by both the chemical (ΔpH) and electrical (Δψ) components of the proton electrochemical gradient (ΔμH+) established by a vacuolar H+‐ATPase [372]. However, one study, [286], 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 [169, 595]. VIAAT knock out mice die between embryonic day 18.5 and birth [570]. In cultures of spinal cord neurones established from earlier embryos, the co‐release of of GABA and glycine from synaptic vesicles is drastically reduced, providing direct evidence for the role of VIAAT in the sequestration of both transmitters [466, 570].

424Anne C et al. (2014) Vesicular neurotransmitter transporters: mechanistic aspects. Curr Top Membr 73: 149‐74 [PMID:24745982]

425Schiöth HB et al. (2013) Evolutionary origin of amino acid transporter families SLC32, SLC36 and SLC38 and physiological, pathological and therapeutic aspects. Mol. Aspects Med. 34: 571‐85 [PMID:23506890]

426Acetylation of proteins is a post‐translational modification mediated by specific acetyltransferases, using the donor acetyl CoA. SLC33A1/AT1 is a putative 11 TM transporter present on the endoplasmic reticulum, expressed in all tissues, but particularly abundant in the pancreas [293], which imports cytosolic acetyl CoA into these intracellular organelles.

427In heterologous expression studies, acetyl CoA transport through AT1 was inhibited by coenzyme A, but not acetic acid, ATP or UDP‐galactose[282]. A loss‐of‐function mutation in ACATN1/SLC33A1 has been associated with spastic paraplegia (SPG42, [349]), although this observation could not be replicated in a subsequent study [478].

428Hirabayashi Y et al. (2004) The acetyl‐CoA transporter family SLC33. Pflugers Arch. 447: 760‐2 [PMID:12739170]

429Hirabayashi Y et al. (2013) The acetyl‐CoA transporter family SLC33. Mol. Aspects Med. 34: 586‐9 [PMID:23506891]

430The 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 [15].

431These transporters can be inhibited by foscarnet, in contrast to type III sodium‐phosphate cotransporters, the SLC20 family.

432Biber J et al. (2013) Phosphate transporters and their function. Annu. Rev. Physiol. 75: 535‐50 [PMID:23398154]

433Forster IC et al. (2013) Phosphate transporters of the SLC20 and SLC34 families. Mol. Aspects Med. 34: 386‐95 [PMID:23506879]

434Shobeiri N et al. (2013) Phosphate: an old bone molecule but new cardiovascular risk factor. Br J Clin Pharmacol [PMID:23506202]

435Wagner CA et al. (2014) The SLC34 family of sodium‐dependent phosphate transporters. Pflugers Arch. 466: 139‐53 [PMID:24352629]

436Glycoprotein 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.

437Ishida N et al. (2004) Molecular physiology and pathology of the nucleotide sugar transporter family (SLC35). Pflugers Arch. 447: 768‐75 [PMID:12759756]

438Orellana A. (2016) Overview of Nucleotide Sugar Transporter Gene Family Functions Across Multiple Species. J Mol Biol 428: 3150‐65 [PMID:27261257]

439Song Z. (2013) Roles of the nucleotide sugar transporters (SLC35 family) in health and disease. Mol. Aspects Med. 34: 590‐600 [PMID:23506892]

440Members 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, 461]. PAT2 is expressed at the apical membrane of the renal proximal tubule [70] and at the plasma‐membrane in brown/beige adipocytes [539]. More comprehensive lists of substrates can be found within the reviews under Further Reading and in the references.

441Schiöth HB et al. (2013) Evolutionary origin of amino acid transporter families SLC32, SLC36 and SLC38 and physiological, pathological and therapeutic aspects. Mol. Aspects Med. 34: 571‐85 [PMID:23506890]

442Thwaites DT et al. (2011) The SLC36 family of proton‐coupled amino acid transporters and their potential role in drug transport. Br. J. Pharmacol. 164: 1802‐16 [PMID:21501141]

443Thwaites DT et al. (2007) Deciphering the mechanisms of intestinal imino (and amino) acid transport: the redemption of SLC36A1. Biochim. Biophys. Acta 1768: 179‐97 [PMID:17123464]

444The 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.

445Chou JY et al. (2014) The SLC37 family of sugar‐phosphate/phosphate exchangers. Curr Top Membr 73: 357‐82 [PMID:24745989]

446Chou JY et al. (2013) The SLC37 family of phosphate‐linked sugar phosphate antiporters. Mol. Aspects Med. 34: 601‐11 [PMID:23506893]

447The SLC38 family of transporters appears to be responsible for the functionally‐defined system A and system N mechanisms of amino acid transport and are mostly expressed in the CNS. Two distinct subfamilies are identifiable within the SLC38 transporters. SNAT1, SNAT2 and SNAT4 appear to resemble system A transporters in accumulating neutral amino acids under the influence of the sodium gradient. SNAT3 and SNAT5 appear to resemble system N transporters in utilizing proton co‐transport to accumulate amino acids. The predicted membrane topology is of 11 TM domains with an extracellular C‐terminus and intracellular N‐terminus [477].

448Bhutia, YD et al. (2016) Glutamine transporters in mammalian cells and their functions in physiology and cancer. Biochim Biophys Acta 1863: 2531‐9 [PMID:26724577]

449Bröer S. (2014) The SLC38 family of sodium‐amino acid co‐transporters. Pflugers Arch. 466: 155‐72 [PMID:24193407]

450Bröer S et al. (2011) The role of amino acid transporters in inherited and acquired diseases. Biochem. J. 436: 193‐211 [PMID:21568940]

451Hägglund MG et al. (2011) Identification of SLC38A7 (SNAT7) protein as a glutamine transporter expressed in neurons. J. Biol. Chem. 286: 20500‐11 [PMID:21511949]

452Schiöth HB et al. (2013) Evolutionary origin of amino acid transporter families SLC32, SLC36 and SLC38 and physiological, pathological and therapeutic aspects. Mol. Aspects Med. 34: 571‐85 [PMID:23506890]

453Along with the SLC30 family, SLC39 family members regulate zinc movement in cells. SLC39 metal ion transporters accumulate zinc into the cytosol. Membrane topology modelling suggests the presence of eight TM regions with both termini extracellular or in the lumen of intracellular organelles. The mechanism for zinc transport for many members is unknown but appears to involve co‐transport of bicarbonate ions [209, 354].

454Zinc fluxes may be monitored through the use of radioisotopic Zn‐65 or the fluorescent dye FluoZin 3.

455The bicarbonate transport inhibitor DIDS has been reported to inhibit cation accumulation through ZIP14 [209].

456Hojyo S et al. (2016) Zinc transporters and signaling in physiology and pathogenesis. Arch Biochem Biophys 611: 43‐50 [PMID:27394923]

457Jeong J et al. (2013) The SLC39 family of zinc transporters. Mol. Aspects Med. 34: 612‐9 [PMID:23506894]

458Kambe T et al. (2014) Current understanding of ZIP and ZnT zinc transporters in human health and diseases. Cell. Mol. Life Sci. 71: 3281‐95 [PMID:24710731]

459Kambe T et al. (2015) The Physiological, Biochemical, and Molecular Roles of Zinc Transporters in Zinc Homeostasis and Metabolism. Physiol. Rev. 95: 749‐784 [PMID:26084690]

460Marger L et al. (2014) Zinc: an underappreciated modulatory factor of brain function. Biochem. Pharmacol. 91: 426‐35 [PMID:25130547]

461Alongside the SLC11 family of proton‐coupled metal transporters, ferroportin allows the accumulation of iron from the diet. Whilst SLC11A2 functions on the apical membrane, ferroportin acts on the basolateral side of the enterocyte, as well as regulating macrophage and placental iron levels. The predicted topology is of 12 TM domains, with intracellular termini [448], with the functional transporter potentially a dimeric arrangement [4, 121]. Ferroportin is essential for iron homeostasis [138]. Ferroportin is expressed on the surface of cells that store and transport iron, such as duodenal enterocytes, hepatocytes, adipocytes and reticuloendothelial macrophages. Levels of ferroportin are regulated by its association with (binding to) hepcidin, a 25 amino acid hormone responsive to circulating iron levels (amongst other signals). Hepcidin binding targets ferroportin for internalisation and degradation, lowering the levels of iron export to the blood. Novel therapeutic agents which stabilise ferroportin or protect it from hepcidin‐induced degradation are being developed as anti‐anemia agents. Anti‐ferroportin monoclonal antibodies are such an agent.

462Hepcidin (HAMP, P81172), cleaved into hepcidin‐25(HAMP, P81172) and hepcidin‐20(HAMP, P81173), is a small protein that increases upon inflammation, binds to ferroportin to regulate its cellular distribution and degradation. Gene disruption in mice results in embryonic lethality [138], while loss‐of‐function mutations in man are associated with haemochromatosis [122].

463McKie AT et al. (2004) The SLC40 basolateral iron transporter family (IREG1/ferroportin/MTP1). Pflugers Arch. 447: 801‐6 [PMID:12836025]

464Montalbetti N et al. (2013) Mammalian iron transporters: families SLC11 and SLC40. Mol. Aspects Med. 34: 270‐87 [PMID:23506870]

465By 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 Mg2+ efflux [317], possibly as a result of co‐expression of particular protein partners (see [462]). Topological modelling suggests 10 TM domains with cytoplasmic C‐ and N‐ termini.

466Payandeh J et al. (2013) The structure and regulation of magnesium selective ion channels. Biochim. Biophys. Acta [PMID:23954807]

467Sahni J et al. (2013) The SLC41 family of MgtE‐like magnesium transporters. Mol. Aspects Med. 34: 620‐8 [PMID:23506895]

468Schweigel‐Röntgen M et al. (2014) SLC41 transporters–molecular identification and functional role. Curr Top Membr 73: 383‐410 [PMID:24745990]

469Rhesus 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.

470Nakhoul NL et al. (2013) Characteristics of mammalian Rh glycoproteins (SLC42 transporters) and their role in acid‐base transport. Mol. Aspects Med. 34: 629‐37 [PMID:23506896]

471Weiner ID et al. (2011) Role of NH3 and NH4+ transporters in renal acid‐base transport. Am. J. Physiol. Renal Physiol. 300: F11‐23 [PMID:21048022]

472Weiner ID et al. (2014) Ammonia transport in the kidney by Rhesus glycoproteins. Am. J. Physiol. Renal Physiol. 306: F1107‐20 [PMID:24647713]

473LAT3 (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 Cl‐ and with two kinetic components [27, 53]. LAT3/SLC43A1 is expressed in human tissues at high levels in the pancreas, liver, skeletal muscle and fetal liver [27] whereas LAT4/SLC43A2 is primarily expressed in the placenta, kidney and peripheral blood leukocytes [53]. SLC43A3 is expressed in vascular endothelial cells [555] but remains to be characterised.

474Covalent modification of LAT3 by N‐ethylmaleimide inhibits its function [27] and at LAT4 inhibits the low‐, but not high‐affinity component of transport [53].

475Bodoy S et al. (2013) The small SLC43 family: facilitator system l amino acid transporters and the orphan EEG1. Mol. Aspects Med. 34: 638‐45 [PMID:23268354]

476Members of the choline transporter‐like family are encoded by five genes (CTL1‐CTL5) with further diversity occurring through alternative splicing of CTL1, 4 and 5 [528]. CTL family members are putative 10TM domain proteins with extracellular termini that mediate Na+‐independent transport of choline with an affinity that is intermediate to that of the high affinity choline transporter CHT1 (SLC5A7) and the low affinity organic‐cation transporters [OCT1 (SLC22A1) and OCT2 (SLC22A2)] [380]. CLT1 is expressed almost ubiquitously in human tissues [568] and mediates choline transport across the plasma and mitochondrial membranes [379]. Transport of choline by CTL2, which in rodents is expressed as two isoforms (CTL2P1 and CLTP2; [318]) in lung, colon, inner ear and spleen and to a lesser extent in brain, tongue, liver, and kidney, has only recently been demonstrated [318, 398]. CTL3‐5 remain to be characterized functionally.

477Data tabulated are features observed for CLT1 endogenous to: rat astrocytes [265]; rat renal tubule epithelial cells [580]; human colon carcinoma cells [320]; human keratinocytes [536] and human neuroblastoma cells [581]. Choline uptake by CLT1 is inhibited by numerous organic cations (e.g. [265, 580, 681]). In the guinea‐pig, CTL2 is a target for antibody‐induced hearing loss [394] and in man, a polymorphism in CTL2 constitutes the human neutrophil alloantigen‐3a (HNA‐3a; [220]).

478Inazu M. (2014) Choline transporter‐like proteins CTLs/SLC44 family as a novel molecular target for cancer therapy. Biopharm Drug Dispos 35: 431‐49 [PMID:24532461]

479Traiffort E et al. (2013) The choline transporter‐like family SLC44: properties and roles in human diseases. Mol. Aspects Med. 34: 646‐54 [PMID:23506897]

480Members 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 [491]. 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. [401]), and polymorphisms in this gene are associated with variations in skin and hair color (e.g. [219]).

481Bartölke R et al. (2014) Proton‐associated sucrose transport of mammalian solute carrier family 45: an analysis in Saccharomyces cerevisiae. Biochem. J. 464: 193‐201 [PMID:25164149]

482Vitavska O et al. (2013) The SLC45 gene family of putative sugar transporters. Mol. Aspects Med. 34: 655‐60 [PMID:23506898]

483Based 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 [434], 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.

484Hou Z et al. (2014) Biology of the major facilitative folate transporters SLC19A1 and SLC46A1. Curr Top Membr 73: 175‐204 [PMID:24745983]

485Matherly LH et al. (2014) The major facilitative folate transporters solute carrier 19A1 and solute carrier 46A1: biology and role in antifolate chemotherapy of cancer. Drug Metab. Dispos. 42: 632‐49 [PMID:24396145]

486Wilson MR et al. (2015) Structural determinants of human proton‐coupled folate transporter oligomerization: role of GXXXG motifs and identification of oligomeric interfaces at transmembrane domains 3 and 6. Biochem. J. [PMID:25877470]

487Zhao R et al. (2011) Mechanisms of membrane transport of folates into cells and across epithelia. Annu. Rev. Nutr. 31: 177‐201 [PMID:21568705]

488Zhao R et al. (2013) Folate and thiamine transporters mediated by facilitative carriers (SLC19A1‐3 and SLC46A1) and folate receptors. Mol. Aspects Med. 34: 373‐85 [PMID:23506878]

489These proton:organic cation exchangers are predicted to have 13 TM segments [603] and are suggested to be responsible for excretion of many drugs in the liver and kidneys.

490DAPI has been used to allow quantification of MATE1 and MATE2‐mediated transport activity [587]. MATE2 and MATE2‐B are inactive splice variants of MATE2‐K [370].

491Damme K et al. (2011) Mammalian MATE (SLC47A) transport proteins: impact on efflux of endogenous substrates and xenobiotics. Drug Metab. Rev. 43: 499‐523 [PMID:21923552]

492Motohashi H et al. (2013) Multidrug and toxin extrusion family SLC47: physiological, pharmacokinetic and toxicokinetic importance of MATE1 and MATE2‐K. Mol. Aspects Med. 34: 661‐8 [PMID:23506899]

493Nies AT et al. (2016) Structure and function of multidrug and toxin extrusion proteins (MATEs) and their relevance to drug therapy and personalized medicine. Arch Toxicol 90: 1555‐84 [PMID:27165417]

494Wagner DJ et al. (2016) Polyspecific organic cation transporters and their impact on drug intracellular levels and pharmacodynamics. Pharmacol Res 111: 237‐46 [PMID:27317943]

495Yonezawa A et al. (2011) Importance of the multidrug and toxin extrusion MATE/SLC47A family to pharmacokinetics, pharmacodynamics/toxicodynamics and pharmacogenomics. Br. J. Pharmacol. 164: 1817‐25 [PMID:21457222]

496HRG1 has been identified as a cell surface and lysosomal heme transporter [439]. In addition, evidence suggests this 4TM‐containing protein associates with the V‐ATPase in lysosomes [407]. 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 [565].

497Khan AA et al. (2013) Heme and FLVCR‐related transporter families SLC48 and SLC49. Mol. Aspects Med. 34: 669‐82 [PMID:23506900]

498FLVCR1 was initially identified as a cell‐surface attachment site for feline leukemia virus subgroup C [509], and later identified as a cell surface accumulation which exports heme from the cytosol [436]. A recent study indicates that an isoform of FLVCR1 is located in the mitochondria, the site of the final steps of heme synthesis, and appears to transport heme into the cytosol [96]. FLVCR‐mediated heme transport is essential for erythropoiesis. Flvcr1 gene mutations have been identified as the cause of PCARP (posterior column ataxia with retinitis pigmentosa (PCARP) [438].There are three paralogs of FLVCR1 in the human genome.

499FLVCR2, most similar to FLVCR1 [351], has been reported to function as a heme importer [141]. In addition, a congenital syndrome of proliferative vasculopathy and hydranencephaly, also known as Fowler's syndrome, is associated with a loss‐of‐function mutation in FLVCR2 [377].

500The functions of the other two members of the SLC49 family, MFSD7 and DIRC2, are unknown, although DIRC2 has been implicated in hereditary renal carcinomas [52].

501Non‐functional splice alternatives of FLVCR1 have been implicated as a cause of a congenital red cell aplasia, Diamond Blackfan anemia[461].

502Khan AA et al. (2013) Heme and FLVCR‐related transporter families SLC48 and SLC49. Mol. Aspects Med. 34: 669‐82 [PMID:23506900]

503Khan AA et al. (2011) Control of intracellular heme levels: heme transporters and heme oxygenases. Biochim. Biophys. Acta 1813: 668‐82 [PMID:21238504]

504A mouse stromal cell cDNA library was used to clone C2.3 [507], later termed Rag1‐activating protein 1, with a sequence homology predictive of a 4TM topology. The plant orthologues, termed SWEETs, appear to be 7 TM proteins, with extracellular N‐termini, and the capacity for bidirectional flux of D‐glucose[88]. Expression of mouse SWEET in the mammary gland was suggestive of a role in Golgi lactose synthesis [88].

505Wright EM. (2013) Glucose transport families SLC5 and SLC50. Mol. Aspects Med. 34: 183‐96 [PMID:23506865]

506Wright EM et al. (2011) Biology of human sodium glucose transporters. Physiol. Rev. 91: 733‐94 [PMID:21527736]

507The SLC51 organic solute transporter family of transporters is a pair of heterodimeric proteins which regulate bile salt movements in the small intestine, bile duct, and liver, as part of the enterohepatic circulation [34, 118]. OSTα/OSTβ is also expressed in steroidogenic cells of the brain and adrenal gland, where it may contribute to steroid movement [168]. Bile acid transport is suggested to be facilitative and independent of sodium, potassium, chloride ions or protons [34, 118]. OSTα/OSTβ heterodimers have been shown to transport [3H]taurocholic acid, [3H]dehydroepiandrosterone sulphate, [3H]estrone‐3‐sulphate, [3H]pregnenolone sulphate and [3H]dehydroepiandrosterone sulphate [34, 118, 168]. OSTα is suggested to be a seven TM protein, while OSTβ is a single TM 'ancillary' protein, both of which are thought to have intracellular C‐termini [347]. Bimolecular fluorescence complementation studies suggest the possibility of OSTα homo‐oligomers, as well as OSTα/OSTβ hetero‐oligomers [100, 347].

508Ballatori N. (2011) Pleiotropic functions of the organic solute transporter Ostα‐Ostβ. Dig Dis 29: 13‐7 [PMID:21691099]

509Ballatori N et al. (2013) The heteromeric organic solute transporter, OSTα‐OSTβ/SLC51: a transporter for steroid‐derived molecules. Mol. Aspects Med. 34: 683‐92 [PMID:23506901]

510Dawson PA. (2011) Role of the intestinal bile acid transporters in bile acid and drug disposition. Handb Exp Pharmacol 169‐203 [PMID:21103970]

511riboflavin, also known as vitamin B2, is a precursor of the enzyme cofactors flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD). Riboflavin transporters are predicted to possess 10 or 11 TM segments.

512Although expressed elsewhere, RFVT3 is found on the luminal surface of intestinal epithelium and is thought to mediate uptake of dietary riboflavin, while RFVT1 and RFVT2 are thought to allow movement from the epithelium into the blood.

513Yonezawa A et al. (2013) Novel riboflavin transporter family RFVT/SLC52: identification, nomenclature, functional characterization and genetic diseases of RFVT/SLC52. Mol. Aspects Med. 34: 693‐701 [PMID:23506902]

514The 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.

515Hagenbuch B et al. (2013) The SLCO (former SLC21) superfamily of transporters. Mol. Aspects Med. 34: 396‐412 [PMID:23506880]

516Lee HH et al. (2017) Interindividual and interethnic variability in drug disposition: polymorphisms in organic anion transporting polypeptide 1B1 (OATP1B1; SLCO1B1). Br J Clin Pharmacol 83: 1176‐1184 [PMID:27936281]

517Murray M et al. (2017) Trafficking and other regulatory mechanisms for organic anion transporting polypeptides and organic anion transporters that modulate cellular drug and xenobiotic influx and that are dysregulated in disease. Br J Pharmacol 174 1908‐1924 [PMID:28299773]

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