The SLC5 family of sodium-dependent transporters includes, in mammals, the Na⁺/substrate co-transporters for choline, glucose (e.g. D-glucose), monocarboxylates, myo-inositol and iodide [15-16,36-37]. 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 [1].

The high affinity, hemicholinium-3-sensitive, choline transporter (CHT) is expressed mainly in cholinergic neurones on nerve cell terminals and synaptic vesicles (keratinocytes being an additional location). In autonomic neurones, expression of CHT requires an activity-dependent retrograde signal from postsynaptic neurones [24]. Through recapture of choline generated by the hydrolysis of ACh by acetylcholinesterase, CHT serves to maintain acetylcholine synthesis within the presynaptic terminal [15]. 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 [14]. 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 [34].

K_i and K_D values for hemicholinium-3 listed in the table are for human CHT expressed in Xenopus laevis oocytes [27], or COS-7 cells [3]. 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.

Detailed characterisation of members of the hexose transporter family is limited to SGLT1, 2 and 3, which are all inhibited in a competitive manner by phlorizin, a natural dihydrocholine glucoside, that exhibits modest selectivity towards SGLT2 (see [36] 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 [11].

Recognition and transport of substrate by SGLTs requires that the sugar is a pyranose. De-oxyglucose derivatives have reduced affinity for SGLT1, but the replacement of the sugar equatorial hydroxyl group by fluorine at some positions, excepting C2 and C3, is tolerated (see [36] 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 [21]. Selective blockers of SGLT2, and thus blocking ~50% of renal glucose reabsorption, are in development for the treatment of diabetes (e.g. [7]).

The sodium-iodide symporter (NIS) is an iodide transporter found principally in the thyroid gland where it mediates the accumulation of iodide within thyrocytes. Transport of iodide 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 iodide required for the synthesis of the thyroid hormones triiodothyronine (T3) and thyroxine (T4) [5]. NIS is also expressed in the salivary glands, gastric mucosa, intestinal enterocytes and lactating breast. NIS mediates iodide absorption in the intestine and iodide 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 [29]. 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 [16]. 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 [16]. 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 [18]. 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 [26]. 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 [32]. SMCT1 also functions as a tumour suppressor in the colon as well as in various other non-colonic tissues [17]. 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 [33]; 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 [16-17,19]. 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 [31].

iodide, perchlorate, thiocyanate and nitrate are competitive substrate inhibitors of NIS [12]. lipoic acid appears to act as a competitive substrate inhibitor of SMVT [35] and the anticonvulsant drugs primidone and carbamazepine competitively block the transport of biotin by brush border vesicles prepared from human intestine [30].

Three different mammalian myo-inositol cotransporters are currently known; two are the Na⁺-coupled SMIT1 and SMIT2 tabulated below and the third is proton-coupled HMIT (SLC2A13). SMIT1 and SMIT2 have a widespread and overlapping tissue location but in polarized cells, such as the Madin-Darby canine kidney cell line, they segregate to the basolateral and apical membranes, respectively [4]. 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 [2].

The 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 [9,20]. 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 [25].

Abramson, J; Wright, EM. (2009) Structure and function of Na(+)-symporters with inverted repeats. Curr. Opin. Struct. Biol., 19 (4): 425-32. [PMID:19631523]

Amenta, F; Tayebati, SK. (2008) Pathways of acetylcholine synthesis, transport and release as targets for treatment of adult-onset cognitive dysfunction. Curr. Med. Chem., 15 (5): 488-98. [PMID:18289004]

Bailey, CJ. (2011) Renal glucose reabsorption inhibitors to treat diabetes. Trends Pharmacol. Sci., 32 (2): 63-71. [PMID:21211857]

Bazalakova, MH; Blakely, RD. (2006) The high-affinity choline transporter: a critical protein for sustaining cholinergic signaling as revealed in studies of genetically altered mice. Handb Exp Pharmacol,  (175): 525-44. [PMID:16722248]

Bizhanova, A; Kopp, P. (2009) Minireview: The sodium-iodide symporter NIS and pendrin in iodide homeostasis of the thyroid. Endocrinology, 150 (3): 1084-90. [PMID:19196800]

Bołdys, A; Okopień, B. (2009) Inhibitors of type 2 sodium glucose co-transporters--a new strategy for diabetes treatment. Pharmacol Rep, 61 (5): 778-84. [PMID:19904000]

Chao, EC; Henry, RR. (2010) SGLT2 inhibition--a novel strategy for diabetes treatment. Nat Rev Drug Discov, 9 (7): 551-9. [PMID:20508640]

Ferguson, SM; Blakely, RD. (2004) The choline transporter resurfaces: new roles for synaptic vesicles?. Mol. Interv., 4 (1): 22-37. [PMID:14993474]

Ganapathy, V; Thangaraju, M; Gopal, E; Martin, PM; Itagaki, S; Miyauchi, S; Prasad, PD. (2008) Sodium-coupled monocarboxylate transporters in normal tissues and in cancer. AAPS J, 10 (1): 193-9. [PMID:18446519]

Ganapathy, V; Thangaraju, M; Prasad, PD. (2009) Nutrient transporters in cancer: relevance to Warburg hypothesis and beyond. Pharmacol. Ther., 121 (1): 29-40. [PMID:18992769]

Ghosh, RK; Ghosh, SM; Chawla, S; Jasdanwala, SA. (2011) SGLT2 Inhibitors: A New Emerging Therapeutic Class in the Treatment of Type 2 Diabetes Mellitus. J Clin Pharmacol,  [Epub ahead of print]. [PMID:21543663]

Kinne, RK; Castaneda, F. (2011) SGLT inhibitors as new therapeutic tools in the treatment of diabetes. Handb Exp Pharmacol,  (203): 105-26. [PMID:21484569]

Okuda, T; Haga, T. (2003) High-affinity choline transporter. Neurochem. Res., 28 (3-4): 483-8. [PMID:12675135]

Ribeiro, FM; Black, SA; Prado, VF; Rylett, RJ; Ferguson, SS; Prado, MA. (2006) The "ins" and "outs" of the high-affinity choline transporter CHT1. J. Neurochem., 97 (1): 1-12. [PMID:16524384]

Sabino-Silva, R; Mori, RC; David-Silva, A; Okamoto, MM; Freitas, HS; Machado, UF. (2010) The Na(+)/glucose cotransporters: from genes to therapy. Braz. J. Med. Biol. Res., 43 (11): 1019-26. [PMID:21049241]

Said, HM. (2009) Cell and molecular aspects of human intestinal biotin absorption. J. Nutr., 139 (1): 158-62. [PMID:19056639]

Sarter, M; Parikh, V. (2005) Choline transporters, cholinergic transmission and cognition. Nat. Rev. Neurosci., 6 (1): 48-56. [PMID:15611726]

Uldry, M; Thorens, B. (2004) The SLC2 family of facilitated hexose and polyol transporters. Pflugers Arch., 447 (5): 480-9. [PMID:12750891]

Wright, EM; Loo, DD; Hirayama, BA. (2011) Biology of human sodium glucose transporters. Physiol. Rev., 91 (2): 733-94. [PMID:21527736]

Wright, EM; Loo, DD; Hirayama, BA; Turk, E. (2004) Surprising versatility of Na+-glucose cotransporters: SLC5. Physiology (Bethesda), 19: 370-6. [PMID:15546855]

Wright, EM; Turk, E. (2004) The sodium/glucose cotransport family SLC5. Pflugers Arch., 447 (5): 510-8. [PMID:12748858]

1. Abramson, J; Wright, EM. (2009) Structure and function of Na(+)-symporters with inverted repeats. Curr. Opin. Struct. Biol., 19 (4): 425-32. [PMID:19631523]

2. Aouameur, R; Da Cal, S; Bissonnette, P; Coady, MJ; Lapointe, JY. (2007) SMIT2 mediates all myo-inositol uptake in apical membranes of rat small intestine. Am. J. Physiol. Gastrointest. Liver Physiol., 293 (6): G1300-7. [PMID:17932225]

3. Apparsundaram, S; Ferguson, SM; George, AL; Blakely, RD. (2000) Molecular cloning of a human, hemicholinium-3-sensitive choline transporter. Biochem. Biophys. Res. Commun., 276 (3): 862-7. [PMID:11027560]

4. Bissonnette, P; Coady, MJ; Lapointe, JY. (2004) Expression of the sodium-myo-inositol cotransporter SMIT2 at the apical membrane of Madin-Darby canine kidney cells. J. Physiol. (Lond.), 558 (Pt 3): 759-68. [PMID:15181167]

5. Bizhanova, A; Kopp, P. (2009) Minireview: The sodium-iodide symporter NIS and pendrin in iodide homeostasis of the thyroid. Endocrinology, 150 (3): 1084-90. [PMID:19196800]

6. Bourgeois, F; Coady, MJ; Lapointe, JY. (2005) Determination of transport stoichiometry for two cation-coupled myo-inositol cotransporters: SMIT2 and HMIT. J. Physiol. (Lond.), 563 (Pt 2): 333-43. [PMID:15613375]

7. Chao, EC; Henry, RR. (2010) SGLT2 inhibition--a novel strategy for diabetes treatment. Nat Rev Drug Discov, 9 (7): 551-9. [PMID:20508640]

8. Coady, MJ; Wallendorff, B; Bourgeois, F; Charron, F; Lapointe, JY. (2007) Establishing a definitive stoichiometry for the Na+/monocarboxylate cotransporter SMCT1. Biophys. J., 93 (7): 2325-31. [PMID:17526579]

9. Coady, MJ; Wallendorff, B; Gagnon, DG; Lapointe, JY. (2002) Identification of a novel Na+/myo-inositol cotransporter. J. Biol. Chem., 277 (38): 35219-24. [PMID:12133831]

10. de Carvalho, FD; Quick, M. (2011) Surprising substrate versatility in SLC5A6: Na+-coupled I- transport by the human Na+/multivitamin transporter (hSMVT). J. Biol. Chem., 286 (1): 131-7. [PMID:20980265]

11. Diez-Sampedro, A; Hirayama, BA; Osswald, C; Gorboulev, V; Baumgarten, K; Volk, C; Wright, EM; Koepsell, H. (2003) A glucose sensor hiding in a family of transporters. Proc. Natl. Acad. Sci. U.S.A., 100 (20): 11753-8. [PMID:13130073]

12. Dohán, O; Portulano, C; Basquin, C; Reyna-Neyra, A; Amzel, LM; Carrasco, N. (2007) The Na+/I symporter (NIS) mediates electroneutral active transport of the environmental pollutant perchlorate. Proc. Natl. Acad. Sci. U.S.A., 104 (51): 20250-5. [PMID:18077370]

13. Eskandari, S; Loo, DD; Dai, G; Levy, O; Wright, EM; Carrasco, N. (1997) Thyroid Na+/I- symporter. Mechanism, stoichiometry, and specificity. J. Biol. Chem., 272 (43): 27230-8. [PMID:9341168]

14. Ferguson, SM; Bazalakova, M; Savchenko, V; Tapia, JC; Wright, J; Blakely, RD. (2004) Lethal impairment of cholinergic neurotransmission in hemicholinium-3-sensitive choline transporter knockout mice. Proc. Natl. Acad. Sci. U.S.A., 101 (23): 8762-7. [PMID:15173594]

15. Ferguson, SM; Blakely, RD. (2004) The choline transporter resurfaces: new roles for synaptic vesicles?. Mol. Interv., 4 (1): 22-37. [PMID:14993474]

16. Ganapathy, V; Thangaraju, M; Gopal, E; Martin, PM; Itagaki, S; Miyauchi, S; Prasad, PD. (2008) Sodium-coupled monocarboxylate transporters in normal tissues and in cancer. AAPS J, 10 (1): 193-9. [PMID:18446519]

17. Ganapathy, V; Thangaraju, M; Prasad, PD. (2009) Nutrient transporters in cancer: relevance to Warburg hypothesis and beyond. Pharmacol. Ther., 121 (1): 29-40. [PMID:18992769]

18. Gopal, E; Fei, YJ; Miyauchi, S; Zhuang, L; Prasad, PD; Ganapathy, V. (2005) Sodium-coupled and electrogenic transport of B-complex vitamin nicotinic acid by slc5a8, a member of the Na/glucose co-transporter gene family. Biochem. J., 388 (Pt 1): 309-16. [PMID:15651982]

19. Gupta, N; Martin, PM; Prasad, PD; Ganapathy, V. (2006) SLC5A8 (SMCT1)-mediated transport of butyrate forms the basis for the tumor suppressive function of the transporter. Life Sci., 78 (21): 2419-25. [PMID:16375929]

20. Hager, K; Hazama, A; Kwon, HM; Loo, DD; Handler, JS; Wright, EM. (1995) Kinetics and specificity of the renal Na+/myo-inositol cotransporter expressed in Xenopus oocytes. J. Membr. Biol., 143 (2): 103-13. [PMID:7537337]

21. Hummel, CS; Lu, C; Loo, DD; Hirayama, BA; Voss, AA; Wright, EM. (2011) Glucose transport by human renal Na+/D-glucose cotransporters SGLT1 and SGLT2. Am. J. Physiol., Cell Physiol., 300 (1): C14-21. [PMID:20980548]

22. Iwamoto, H; Blakely, RD; De Felice, LJ. (2006) Na+, Cl-, and pH dependence of the human choline transporter (hCHT) in Xenopus oocytes: the proton inactivation hypothesis of hCHT in synaptic vesicles. J. Neurosci., 26 (39): 9851-9. [PMID:17005849]

23. Kanai, Y; Lee, WS; You, G; Brown, D; Hediger, MA. (1994) The human kidney low affinity Na+/glucose cotransporter SGLT2. Delineation of the major renal reabsorptive mechanism for D-glucose. J. Clin. Invest., 93 (1): 397-404. [PMID:8282810]

24. Krishnaswamy, A; Cooper, E. (2009) An activity-dependent retrograde signal induces the expression of the high-affinity choline transporter in cholinergic neurons. Neuron, 61 (2): 272-86. [PMID:19186169]

25. Lin, X; Ma, L; Fitzgerald, RL; Ostlund, RE. (2009) Human sodium/inositol cotransporter 2 (SMIT2) transports inositols but not glucose in L6 cells. Arch. Biochem. Biophys., 481 (2): 197-201. [PMID:19032932]

26. Miyauchi, S; Gopal, E; Fei, YJ; Ganapathy, V. (2004) Functional identification of SLC5A8, a tumor suppressor down-regulated in colon cancer, as a Na(+)-coupled transporter for short-chain fatty acids. J. Biol. Chem., 279 (14): 13293-6. [PMID:14966140]

27. Okuda, T; Haga, T. (2000) Functional characterization of the human high-affinity choline transporter. FEBS Lett., 484 (2): 92-7. [PMID:11068039]

28. Prasad, PD; Srinivas, SR; Wang, H; Leibach, FH; Devoe, LD; Ganapathy, V. (2000) Electrogenic nature of rat sodium-dependent multivitamin transport. Biochem. Biophys. Res. Commun., 270 (3): 836-40. [PMID:10772912]

29. Said, HM. (2009) Cell and molecular aspects of human intestinal biotin absorption. J. Nutr., 139 (1): 158-62. [PMID:19056639]

30. Said, HM; Redha, R; Nylander, W. (1989) Biotin transport in the human intestine: inhibition by anticonvulsant drugs. Am. J. Clin. Nutr., 49 (1): 127-31. [PMID:2911998]

31. Singh, N; Thangaraju, M; Prasad, PD; Martin, PM; Lambert, NA; Boettger, T; Offermanns, S; Ganapathy, V. (2010) Blockade of dendritic cell development by bacterial fermentation products butyrate and propionate through a transporter (Slc5a8)-dependent inhibition of histone deacetylases. J. Biol. Chem., 285 (36): 27601-8. [PMID:20601425]

32. Thangaraju, M; Ananth, S; Martin, PM; Roon, P; Smith, SB; Sterneck, E; Prasad, PD; Ganapathy, V. (2006) c/ebpdelta Null mouse as a model for the double knock-out of slc5a8 and slc5a12 in kidney. J. Biol. Chem., 281 (37): 26769-73. [PMID:16873376]

33. Thangaraju, M; Gopal, E; Martin, PM; Ananth, S; Smith, SB; Prasad, PD; Sterneck, E; Ganapathy, V. (2006) SLC5A8 triggers tumor cell apoptosis through pyruvate-dependent inhibition of histone deacetylases. Cancer Res., 66 (24): 11560-4. [PMID:17178845]

34. Traiffort, E; Ruat, M; O'Regan, S; Meunier, FM. (2005) Molecular characterization of the family of choline transporter-like proteins and their splice variants. J. Neurochem., 92 (5): 1116-25. [PMID:15715662]

35. Wang, H; Huang, W; Fei, YJ; Xia, H; Yang-Feng, TL; Leibach, FH; Devoe, LD; Ganapathy, V; Prasad, PD. (1999) Human placental Na+-dependent multivitamin transporter. Cloning, functional expression, gene structure, and chromosomal localization. J. Biol. Chem., 274 (21): 14875-83. [PMID:10329687]

36. Wright, EM; Loo, DD; Hirayama, BA. (2011) Biology of human sodium glucose transporters. Physiol. Rev., 91 (2): 733-94. [PMID:21527736]

37. Wright, EM; Turk, E. (2004) The sodium/glucose cotransport family SLC5. Pflugers Arch., 447 (5): 510-8. [PMID:12748858]