Pflügers Archiv

, Volume 447, Issue 5, pp 510–518 | Cite as

The sodium/glucose cotransport family SLC5

  • Ernest M. Wright
  • Eric Turk
The ABC of Solute Carriers Guest Editor: Matthias A. Hediger


The sodium/glucose cotransporter family (SLCA5) has 220 or more members in animal and bacterial cells. There are 11 human genes expressed in tissues ranging from epithelia to the central nervous system. The functions of nine have been revealed by studies using heterologous expression systems: six are tightly coupled plasma membrane Na+/substrate cotransporters for solutes such as glucose, myo-inositol and iodide; one is a Na+/Cl/choline cotransporter; one is an anion transporter; and another is a glucose-activated ion channel. The exon organization of eight genes is similar in that each comprises 14–15 exons. The choline transporter (CHT) is encoded in eight exons and the Na+-dependent myo-inositol transporter (SMIT) in one exon. Mutations in three genes produce genetic diseases (glucose-galactose malabsorption, renal glycosuria and hypothyroidism). Members of this family are multifunctional membrane proteins in that they also behave as uniporters, urea and water channels, and urea and water cotransporters. Consequently it is a challenge to determine the role(s) of these genes in human physiology and pathology.


Cotransporters Glucose Iodide Choline Vitamins Inositol 



Our research on SLC5 over the past two decades has been supported by grants from the National Institutes of Health (DK19567; DK44602 and DK44582) and has been made possible by the talent of students, fellows and collaborators cited in the references.


  1. 1.
    Apparsundaram S, Ferguson SM, George AL, Blakely RD (2001) Molecular cloning of a human, hemicholinium-3-sensitive choline transporter. Biochem Biophys Res Commun 276:862–867CrossRefGoogle Scholar
  2. 2.
    Berry GT, Mallee JJ, Kwon HM, Rim JS, Mulla WR, Muenke M, Spinner NB (1995) The human osmoregulatory Na+/myo-inositol cotransporter gene (SLC5A3): molecular cloning and localization to chromosome 21. Genomics 25:507–513CrossRefPubMedGoogle Scholar
  3. 3.
    Birnir B, Lee H-S, Hediger MA, Wright EM (1990) Expression and characterization of the intestinal Na+/glucose cotransporter in COS-7 cells. Biochim Biophys Acta 1048:100–104CrossRefPubMedGoogle Scholar
  4. 4.
    Birnir B, Loo DDF, Wright EM (1991) Voltage clamp studies of the Na+/glucose cotransporter cloned from rabbit small intestine. Pflugers Arch 418:79–85PubMedGoogle Scholar
  5. 5.
    Briasoulis E, Judson I, Pavlidis N, Beale P, Wanders J, Groot Y, Veerman G, Schuessler M, Niebch G, Siamopoulos K, Tzamakou E, Rammou D, Wolf L, Walker R, Hanauske A (2001) Phase I trial of 6-hour infusion of glufosfamide, a new alkylating agent with potentially enchanced selectivity for tumors that overexpress transmembrane glucose transporters: a study of the European Organization for Research and Treatment of cancer early clinical studies group. J Clin Oncol 18:3535–3544Google Scholar
  6. 6.
    Coady MJ, Wallendorff B, Gagnon DG, Lapointe J-Y (2002). Identification of a novel Na+/myo-inositol cotransporter. J Biol Chem 277:35219–35224CrossRefPubMedGoogle Scholar
  7. 7.
    Crane RK, Miller D, Bihler I (1961) The restrictions on possible mechanisms of intestinal active transport of sugars. In: Kleinzeller A, Kotyk A (eds) Membrane transport and metabolism. Czechoslovak Academy of Sciences, Prague, (Academic Press, London), pp 439–449Google Scholar
  8. 8.
    Dai G, Levy O, Carrasco N (1996) Cloning and characterization of the thyroid iodide transporter. Nature 379:458–464PubMedGoogle Scholar
  9. 9.
    De La Vieja A, Dohan O, Levy O, Carrasco N (2001) Molecular analysis of the sodium/iodide symporter: impact on thyroid and extrathyroid pathophysiology. Physiol Rev 80:1083–1105Google Scholar
  10. 10.
    Diez-Sampedro A, Wright EM, Hirayama BA (2001) Residue 457 controls sugar binding and transport in the Na+/glucose cotransporter. J Biol Chem 276:49188–49194CrossRefPubMedGoogle Scholar
  11. 11.
    Diez-Sampedro A, Hirayama BA, Oswald C, Gorboulev V, Baumgerten K, Volk C, Wright EM, Koepsell H (2003) A sugar sensor hiding in a family of transporters. SubmittedGoogle Scholar
  12. 12.
    Dunham I, Shimizu N, Roe BA, Chissoe S, Hunt AR, Collins JE, Bruskiewich R, Beare DM, Clamp M, Smink LJ, Ainscough R, Almeida JP, Babbage A, Bagguley C, Bailey J, Barlow K, Bates KN, Beasley O, Bird CP, Blakey S, Bridegmann AM, Buck D, Burgess J, Burrill WD, O’Brien KP (1999) The DNA sequence of human chromosome 22. Nature 402:489–95CrossRefPubMedGoogle Scholar
  13. 13.
    Eskandari S, Loo DDF, Dai G, Levy R, Wright EM, Carrasco N (1997) Thyroid Na+/I symporter: mechanisms, stoichiometry, and specificity. J Biol Chem 272:27230–27238PubMedGoogle Scholar
  14. 14.
    Eskandari S, Wright EM, Kreman M, Starace DM, Zampighi GA (1998) Structural analysis of cloned membrane proteins by freeze-fracture electron microscopy. Proc Natl Acad Sci USA 95:11235–11240CrossRefPubMedGoogle Scholar
  15. 15.
    Hager K, Hazama A, Kwon HM, Loo DDF, Handler JS, Wright EM (1995) Kinetics and specificity of the renal Na+/myo-inositol cotransporter expressed in Xenopus oocytes. J Membr Biol 143:103–113PubMedGoogle Scholar
  16. 16.
    Handler JS, Kwon HM (2001) Transcriptional regulation by changes in tonicity. Kidney Int 60:408–411CrossRefPubMedGoogle Scholar
  17. 17.
    Hediger MA, Coady MJ, Ikeda TS, Wright EM (1987) Expression cloning and cDNA sequencing of the Na+/glucose cotransporter. Nature 330:379–381PubMedGoogle Scholar
  18. 18.
    Hediger MA, Ikeda T, Coady M, Gundersen CB, Wright EM (1987) Expression of size selected mRNA encoding the intestinal Na/glucose cotransporter in Xenopus laevis oocytes. Proc Natl Acad Sci USA 84:2634–2637PubMedGoogle Scholar
  19. 19.
    Hediger MA, Turk E, Wright EM (1989) Homology of the human intestinal Na+/glucose and E. coli Na+/proline cotransporters. Proc Natl Acad Sci USA 86:5748–5752PubMedGoogle Scholar
  20. 20.
    Hirayama BA, Lostao MP, Panayotova-Heiermann M, Loo DDF, Turk E, Wright EM (1996) Kinetic and specificity differences between rat, human and rabbit Na/glucose cotransporters (SGLT1). Am J Physiol 270:G919–G926PubMedGoogle Scholar
  21. 21.
    Hirayama BA, Loo DDF, Wright EM (1997) Cation effects on protein conformation and transport in the Na+/glucose cotransporter. J Biol Chem 272:2110–2115CrossRefPubMedGoogle Scholar
  22. 22.
    Hirayama BA, Diez-Sampedro A, Wright EM (2001) Common mechanisms of inhibition for the Na+/glucose (hSGLT1) and Na+/Cl/GABA (hGAT1) cotransporters. Br J Pharmacol 134:484–495PubMedGoogle Scholar
  23. 23.
    Hirsch JR, Loo DDF, Wright EM (1996) Regulation of Na+/glucose cotransporter expression by protein kinases in Xenopus laevis oocytes. J Biol Chem 271:14740–4746CrossRefPubMedGoogle Scholar
  24. 24.
    Hirschorn N, Greenough WB (1991) Progress in oral rehydration therapy. Sci Am 264:50–56PubMedGoogle Scholar
  25. 25.
    Ikeda TS, Hwang E-S, Coady MJ, Hirayama BA, Hediger MA, Wright EM (1989) Characterization of a Na+/glucose cotransporter cloned from rabbit small intestine. J Membr Biol 110:87–95PubMedGoogle Scholar
  26. 26.
    Jung H (2002) The sodium/substrate symporter family: structural and functional features. FEBS Lett 529:73–77CrossRefPubMedGoogle Scholar
  27. 27.
    Kanai Y, Lee W-S, You G, Brown D, Hediger MA (1994) The human kidney low affinity Na+/glucose cotransporter SGLT2. J Clin Invest 93:397–404PubMedGoogle Scholar
  28. 28.
    Kasahara M, Maeda M, Hayash S, Mori Y, Abe T (2001) A missense mutation in the Na+/glucose cotransporter gene SGLT1 is a patient with congenital glucose-galactose malabsorption: normal trafficking but inactivation of the mutant protein. Biochim Biophys Acta 1536:141–147PubMedGoogle Scholar
  29. 29.
    Kwon H, Yamauchi A, Uchida S, Preston A, Garcia-Perez A, Burg MB, Handler J (1992) Cloning of the cDNa for a Na+/myo-inositol cotransporter, a hypertonicity stress protein. J Biol Chem 267:6297–6301PubMedGoogle Scholar
  30. 30.
    Lam JT, Martin MG, Turk E, Bosshard NU, Steinmann B, Wright EM (1998) Missense mutations in SGLT1 cause glucose-galactose malabsorption by trafficking defects. Biochim Biophys Acta 1453:297–303Google Scholar
  31. 31.
    Le Coutre J, Turk E, Kaback RH, Wright EM (2002) Ligand-induced differences in secondary structure of the Vibrio parahaemolyticus Na+/galactose cotransporter. Biochemistry 41:8082–8086CrossRefPubMedGoogle Scholar
  32. 32.
    Lescale-Matys L, Dyer J, Scott D, Wright EM Shirazi-Beechey SP (1993) Regulation of ovine intestinal Na+/glucose cotransporter (SGLT1) by sugar is dissociated from mRNA abundance. Biochem J 291:435–440PubMedGoogle Scholar
  33. 33.
    Leung D, Loo DDF, Hirayama BA, Zeuthen T, Wright EM (2000) Urea transport by cotransporters. J Physiol (Lond) 528:251–257Google Scholar
  34. 34.
    Loo DDF, Hazama A, Supplisson S, Turk E, Wright EM (1993) Relaxation kinetics of the Na+/glucose cotransporter. Proc Natl Acad Sci USA 90:5767–5771PubMedGoogle Scholar
  35. 35.
    Loo DDF, Zeuthen T, Chandy G, Wright EM (1996) Cotransport of water by the Na+/glucose cotransporter. Proc Natl Acad Sci USA 93:13367–13370CrossRefPubMedGoogle Scholar
  36. 36.
    Loo DDF, Hirayama BA, Gallardo EM, Lam JT, Turk E, Wright EM (1998) Conformational changes couple Na+ and glucose transport. Proc Natl Acad Sci USA 95:7789–7794CrossRefPubMedGoogle Scholar
  37. 37.
    Loo DDF, Hirayama BA, Meinild AK, Chandy G, Zeuthen Z, Wright EM (1999) Passive water and ion transport by cotransporters. J Physiol (Lond) 518:195–202Google Scholar
  38. 38.
    Loo DDF, Wright EM, Zeuthen T (2002) Water pumps. J Physiol (Lond) 542:53–60Google Scholar
  39. 39.
    Mallee JJ, Atta MG, Lorica V, Rim JS, Kwon HM, Lucente AD, Wang Y, Berry GT (1997) The structural organization of the human Na+/myo-inositol cotransporter (SLC5A3) gene and characterization of the promoter. Genomics 46:459–465CrossRefPubMedGoogle Scholar
  40. 40.
    Martin MG, Turk E, Lostao MP, Kerner C, Wright EM (1996) Defects in Na+/glucose cotransporter (SGLT1) trafficking and function cause glucose-galactose malabsorption. Nat Genet 12:216–220PubMedGoogle Scholar
  41. 41.
    Martin MG, Lostao MP, Turk E, Lam J, Kreman M, Wright EM (1997) Compound missense mutations in the sodium/D-glucose cotransporter (SGLT1) results in trafficking defects. Gastroenterology 112:1206–1212PubMedGoogle Scholar
  42. 42.
    Martin MG, Wang J, Solorzano-Vargas RS, Lam JT, Turk E, Wright EM (2000) Regulation of the human Na+/glucose cotransporter gene (SGLT1) by HNF-1 and the Sp family of transcriptional factors. Am J Physiol 278:G591–G603Google Scholar
  43. 43.
    Meinild A-K, Klaerke D, Loo DDF, Wright EM, Zeuthen T (1998) The human Na+/glucose cotransporter is a molecular water pump. J Physiol (Lond) 508:15–21Google Scholar
  44. 44.
    Meinild AK, Hirayama BA, Wright EM, Loo DDF (2002) Fluorescence studies of ligand-induced conformational changes of the Na+/glucose cotransporter. Biochemistry 41:1250–1258CrossRefPubMedGoogle Scholar
  45. 45.
    Nagata K, Hori N, Sato K, Ohta K, Tanaka H, Hiji Y (1999) Cloning and functional expression of an SGLT-1-like protein from the Xenopus laevis intestine. Am J Physiol 276:G1251–G1259PubMedGoogle Scholar
  46. 46.
    Nunoi K, Yasuda K, Adachi T, Okamoto Y, Shihara N, Uno M, Tamon A, Suzuki N, Oku A, Tsuda K (2002) Beneficial effect of T-1095, a selective inhibitor of renal Na+-glucose cotransporters, on metabolic index and insulin secretion in spontaneously diabetic GK rats. Clin Exp Pharmacol Physiol 29:386–390CrossRefPubMedGoogle Scholar
  47. 47.
    Okuda T, Haga T (2001) Functional characterization of the human high-affinity choline transporter. FEBS Lett 484:92–97CrossRefGoogle Scholar
  48. 48.
    Okuda T, Haga T, Kanai Y, Endou H, Ishihara T, Katsura I (2001) Identification and characterization of the high-affinity choline transporter. Nat Neurosci 3:120–125CrossRefGoogle Scholar
  49. 49.
    Panajotova-Heiermann M, Loo DDF, Klong C-T, Lever JE, Wright EM (1996) Sugar binding to Na+/glucose cotransporters is determined by the C-terminal half of the protein. J Biol Chem 271:10029–10034CrossRefPubMedGoogle Scholar
  50. 50.
    Panayotova-Heiermann M, Eskandari S, Zampighi GA, Wright EM (1997) Five transmembrane helices form the sugar pathway through the Na+/glucose transporter. J Biol Chem 272:20324–20327CrossRefPubMedGoogle Scholar
  51. 51.
    Panayotova-Heiermann M, Leung DW, Hirayama BA, Wright EM (1999) Purification and functional reconstitution of a truncated human Na+/glucose cotransporter (SGLT1) expressed in E. coli. FEBS Lett 459:386–290CrossRefPubMedGoogle Scholar
  52. 52.
    Panayotova-Heiermann M, Wright EM (2001) Mapping the urea channel through the Na+/glucose cotransporter, SGLT1. J Physiol (Lond) 535:419–425Google Scholar
  53. 53.
    Parent L, Supplisson S, Loo DDF, Wright EM (1992) Electrogenic properties of the cloned Na+/glucose cotransporter. Part I. Voltage-clamp studies. J Membr Biol 125:49–62PubMedGoogle Scholar
  54. 54.
    Parent L, Supplisson S, Loo DDF, Wright EM (1992) Electrogenic properties of the cloned Na+/glucose cotransporter: Part II. A transport model under non-rapid-equilibrium conditions. J Membr Biol 125:63–79PubMedGoogle Scholar
  55. 55.
    Peerce BE, Wright EM (1984) Conformational changes in the intestinal brush border Na-glucose cotransporter labeled with fluorescein isothiocyanate. Proc Natl Acad Sci USA 81:2223–2226PubMedGoogle Scholar
  56. 56.
    Porcellati F, Hosaka Y, Hlaing T, Togawa M, Larkin DD, Karihaloo A, Stevens MJ, Killen PD, Greene DA (1999) Alternate splicing in human Na+-MI cotransporter gene yields differentially regulated transport isoforms. Am J Physiol 276:C1325–C1337PubMedGoogle Scholar
  57. 57.
    Prasad PD, Wang HP, Kekuda R, Fujita T, Fei YJ, Devoe LD, Leibach FH, Ganapathy V (1998) Cloning and functional expression of a cDNA encoding a mammalian sodium-dependent vitamin transporter mediating the uptake of pantothenate, biotin, and lipoate. J Biol Chem 273:7501–7506CrossRefPubMedGoogle Scholar
  58. 58.
    Prasad PD, Wang HP, Huang W, Fei YJ, Leibach FH, Devoe LD, Ganapathy V (1999) Molecular and functional characterization of the intestinal Na+-dependent multivitamin transporter. Arch Biochem Biophys 366:95–106PubMedGoogle Scholar
  59. 59.
    Quick M, Loo DDF, Wright EM (2001) Neutralization of a conserved amino acid residue in the human Na+/glucose cotransporter (hSGLT1) generates a glucose-gated H+ channel. J Biol Chem 276:1728–1734CrossRefPubMedGoogle Scholar
  60. 60.
    Riedel C, Dohan O, De la Vieja A, Ginter CS, Carrasco N (2001) Journey of the iodide transporter NIS: from its molecular identification to its clinical role in cancer. Trends Biochem Sci 26:490–496CrossRefPubMedGoogle Scholar
  61. 61.
    Rodriguez AM, Perron B, Lacroix L, Caillou B, Leblanc G, Schlumberger M, Bidart JM, Pourcher T (2002) Identification and characterization of a putative human iodide transporter located at the apical membrane of thyrocytes. J Clin Endocrinol Metab 87:3500–3503PubMedGoogle Scholar
  62. 62.
    Roll P, Massacrier A, Pereira S, Robaglia-Schlupp, A, Cau P, Szepetowski P (2002) New human sodium/glucose cotransporter gene (KST1): identification, characterization, and mutation analysis in ICCA (infantile convulsions and choreoathetosis) and BFIC (benign familial infantile convulsions) families. Gene 285:141–148CrossRefPubMedGoogle Scholar
  63. 63.
    Shirazi-Beechey SP, Hirayama BA, Wang Y, Scott D, Smith MW, Beechey RB, Wright EM (1991) Ontogenic development of the lamb intestinal Na+/glucose cotransporter is regulated by diet. J Physiol (Lond) 437:699–708Google Scholar
  64. 64.
    Schultz SG, PF Curran (1970) Coupled transport of sodium and organic solutes. Physiol Rev 50:637–718PubMedGoogle Scholar
  65. 65.
    Smanik PA, Liu Q, Furminger TL, Ryu K, Xing S, Mazzaferri EL, Jhiang SM (1996) Cloning of the human sodium iodide symporter. Biochem Biophys Res Commun 226:339–345PubMedGoogle Scholar
  66. 66.
    Smanik PA, Ryu K, Theil KS, Mazzaferri EL, Jhiang SM (1997) Expression, exon-intron organization, and chromosome mapping of the human sodium iodide symporter. Endocrinology 138:3555–3558PubMedGoogle Scholar
  67. 67.
    Turk E, Wright EM (1997) Membrane topological motifs in the SGLT cotransporter family. J Membr Biol 159:1–20CrossRefPubMedGoogle Scholar
  68. 68.
    Turk E, Zabel B, Mundlos S, Dyer J, Wright EM (1991) Glucose/galactose malabsorption caused by a defect in the Na+/glucose cotransporter. Nature 350:354–356PubMedGoogle Scholar
  69. 69.
    Turk E, Martin MG, Wright EM (1994) Structure of the human Na+/glucose cotransporter gene SGLTI. J Biol Chem 269:15204–15209PubMedGoogle Scholar
  70. 70.
    Turk E, Kerner, CJ, Lostao MP, Wright EM (1996) Membrane topology of the human Na+/glucose cotransporter SGLT1. J Biol Chem 271:1925–1934CrossRefPubMedGoogle Scholar
  71. 71.
    Turk E, Kim O, leCoutre J, Whitelegge JP, Eskandari S, Lam JT, Kreman M, Zampighi G, Faull KF, Wright EM (2000) Molecular characterization of Vibrio parahaemolyticus vSGLT: a model for sodium-coupled sugar cotransporters. J Biol Chem 275:25711–25716CrossRefPubMedGoogle Scholar
  72. 72.
    Umbach JA, Coady MJ, Wright EM (1990) The intestinal Na+/glucose cotransporter expressed in Xenopus oocytes is electrogenic. Biophys J 57:1217–1224PubMedGoogle Scholar
  73. 73.
    Van de Heuvel LP, Assink K, Willemsen M, Monnens L (2002) Autosomal recessive renal glucosuria attributable to a mutation in the sodium glucose cotransporter (SGLT2). Hum Genet 111:544–547CrossRefPubMedGoogle Scholar
  74. 74.
    Van Sande J, Massart C, Beauwens R, Schoutens A, Costagliola S, Dumont JE, Wolff J (2003) Anion selectivity by the sodium iodide symporter. Endocrinology 144:247–252CrossRefPubMedGoogle Scholar
  75. 75.
    Veyhl M, Wagner K, Volk C, Gorboulev V, Baumgarten K, Weber WM, Schaper M, Bertram B, Wiessler M, Koepsell H (1998) Transport of the new chemotherapeutic agent β-d-glucosylisophosphoramide mustard (D-19575) into tumor cells is mediated by the Na+-d-glucose cotransporter SAAT1. Proc Natl Acad Sci USA 95:2914–2919CrossRefPubMedGoogle Scholar
  76. 76.
    Wang HP, 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 274:14875–14883CrossRefPubMedGoogle Scholar
  77. 77.
    Wells RG, Kanai Y, Pajor AM, Turk E, Wright EM, Hediger MA (1992) The cloning of a human kidney cDNA with similarity to the sodium/glucose cotransporter. Am J Physiol 263:F459–F465PubMedGoogle Scholar
  78. 78.
    Wright EM (2001) Renal Na+/glucose cotransporters. Am J Physiol 280:F10–F18PubMedGoogle Scholar
  79. 79.
    Wright EM, Peerce BE (1984) Identification and conformational changes of the intestinal proline carrier. J Biol Chem 259:14993–14996PubMedGoogle Scholar
  80. 80.
    Wright EM, Hirayama BA, Loo DDF, Turk E, Hager K (1994) Intestinal sugar transport. In: Johnson, LR (ed) Physiology of gastrointestinal tract, 3rd Edn. Raven Press, New York, pp 1751–1772Google Scholar
  81. 81.
    Wright EM, Hirsch JR, Loo DDF, Zampighi GA (1997) Regulation of Na+/glucose cotransporters. J Exp Biol 200:287–293PubMedGoogle Scholar
  82. 82.
    Wright EM, Loo DDF, Panayotova-Heiermann M, Hirayama BA, Turk E, Eskandari S, Lam J (1998) Structure and function of the Na+/glucose cotransporter. Acta Physiol Scand 163:257–264Google Scholar
  83. 83.
    Wright EM, Martin GM, Turk E (2001) Familial glucose-galactose malabsorption and hereditary renal glycosuria. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) Metabolic basis of inherited disease, 8th Edn. McGraw-Hill, New York, pp 4891–4908Google Scholar
  84. 84.
    Wright EM, Turk E, and Martin MG (2002) The molecular basis for glucose-galactose-malabsorption. Cell Biochem Biophys 36:115–121PubMedGoogle Scholar
  85. 85.
    Zampighi GA, Kreman M, Boorer KJ, Loo DDF, Bezanilla F, Chando G, Hall JE, Wright EM (1995) A method for determining the unitary functional capacity of cloned channels and transporters expressed in Xenopus laevis oocytes. J Membr Biol 148:65–78PubMedGoogle Scholar
  86. 86.
    Zampighi GA, Kreman M, Lanzavecchia S, Turk E, Eskandari S, Zampighi L, Wright EM (2002) Structure of functional single AQP0 tetramer inserted in phospholipid membranes. J Mol Biol 325:201–210CrossRefGoogle Scholar

Copyright information

© Springer-Verlag  2004

Authors and Affiliations

  1. 1.Department of PhysiologyDavid Geffen School of Medicine at UCLALos AngelesUSA

Personalised recommendations