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The SLC2 family of facilitated hexose and polyol transporters

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An Erratum to this article was published on 26 March 2004

Abstract

The SLC2 family of glucose and polyol transporters comprises 13 members, the glucose transporters (GLUT) 1–12 and the H+-myo-inositol cotransporter (HMIT). These proteins all contain 12 transmembrane domains with both the amino and carboxy-terminal ends located on the cytoplasmic side of the plasma membrane and a N-linked oligosaccharide side-chain located either on the first or fifth extracellular loop. Based on sequence comparison, the GLUT isoforms can be grouped into three classes: class I comprises GLUT1–4; class II, GLUT6, 8, 10, and 12 and class III, GLUT5, 7, 9, 11 and HMIT. Despite their sequence similarity and the presence of class-specific signature sequences, these transporters carry various hexoses and HMIT is a H+/myo-inositol co-transporter. Furthermore, the substrate transported by some isoforms has not yet been identified. Tissue- and cell-specific expression of the well-characterized GLUT isoforms underlies their specific role in the control of whole-body glucose homeostasis. Numerous studies with transgenic or knockout mice indeed support an important role for these transporters in the control of glucose utilization, glucose storage and glucose sensing. Much remains to be learned about the transport functions of the recently discovered isoforms (GLUT6–13 and HMIT) and their physiological role in the metabolism of glucose, myo-inositol and perhaps other substrates.

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References

  1. Abel ED, Kaulbach HC, Tian R, Hopkins JC, Duffy J, Doetschman T, Minnemann T, Boers ME, Hadro E, Oberste-Berghaus C, Quist W, Lowell BB, Ingwall JS, Kahn BB (1999) Cardiac hypertrophy with preserved contractile function after selective deletion of GLUT4 from the heart. J Clin Invest 104:1703–1714

    CAS  PubMed  Google Scholar 

  2. Abel ED, Peroni O, Kim JK, Kim YB, Boss O, Hadro E, Minnemann T, Shulman GI, Kahn BB (2001) Adipose-selective targeting of the GLUT4 gene impairs insulin action in muscle and liver. Nature 409:729–733

    CAS  PubMed  Google Scholar 

  3. Al-Hasani H, Kunamneni RK, Dawson K, Hinck CS, Muller-Wieland D, Cushman SW (2002) Roles of the N- and C-termini of GLUT4 in endocytosis. J Cell Sci 115:131–140

    CAS  PubMed  Google Scholar 

  4. Baldwin SA, Lienhard GE (1989) Purification and reconstitution of glucose transporter from human erythrocytes. Methods Enzymol 174:39–50

    CAS  PubMed  Google Scholar 

  5. Deleted

  6. Berridge MJ, Downes CP, Hanley MR (1989) Neural and developmental actions of lithium: a unifying hypothesis. Cell 59:411–419

    CAS  PubMed  Google Scholar 

  7. Bilan PJ, Mitsumoto Y, Maher F, Simpson IA, Klip A (1992) Detection of the GLUT3 facilitative glucose transporter in rat L6 muscle cells: regulation by cellular differentiation, insulin and insulin-like growth factor-I. Biochem Biophys Res Commun 186:1129–1137

    CAS  PubMed  Google Scholar 

  8. Birnbaum MJ (1989) Identification of a novel gene encoding an insulin-responsive glucose transporter protein. Cell 57:305–315

    CAS  PubMed  Google Scholar 

  9. Blakemore SJ, Aledo JC, James J, Campbell FC, Lucocq JM, Hundal HS (1995) The GLUT5 hexose transporter is also localized to the basolateral membrane of the human jejunum. Biochem J 309:7–12

    CAS  PubMed  Google Scholar 

  10. Burant CF, Takeda J, Brot-Laroche E, Bell GI, Davidson NO (1992) Fructose transporter in human spermatozoa and small intestine is GLUT5. J Biol Chem 267:14523–14526

    CAS  PubMed  Google Scholar 

  11. Burcelin R, Thorens B (2001) Evidence that extrapancreatic GLUT2-dependent glucose sensors control glucagon secretion. Diabetes 50:1282–1289

    CAS  PubMed  Google Scholar 

  12. Burcelin R, Dolci W, Thorens B (2000) Glucose sensing by the hepatoportal sensor is GLUT2-dependent: in vivo analysis in GLUT2-null mice. Diabetes 49:1643–1648

    CAS  PubMed  Google Scholar 

  13. Carayannopoulos MO, Chi MM, Cui Y, Pingsterhaus JM, McKnight RA, Mueckler M, Devaskar SU, Moley KH (2000) GLUT8 is a glucose transporter responsible for insulin-stimulated glucose uptake in the blastocyst. Proc Natl Acad Sci USA 97:7313–7318

    CAS  PubMed  Google Scholar 

  14. Charron MJ, Brosius FC 3rd, Alper SL, Lodish HF (1989) A glucose transport protein expressed predominately in insulin-responsive tissues. Proc Natl Acad Sci USA 86:2535–2539

    CAS  PubMed  Google Scholar 

  15. Cremona O, De Camilli P (2001) Phosphoinositides in membrane traffic at the synapse. J Cell Sci 114:1041–1052

    CAS  PubMed  Google Scholar 

  16. Dawson PA, Mychaleckyj JC, Fossey SC, Mihic SJ, Craddock AL, Bowden DW (2001) Sequence and functional analysis of GLUT10: a glucose transporter in the Type 2 diabetes-linked region of chromosome 20q12–13.1. Mol Genet Metab 74:186–199

    Article  CAS  PubMed  Google Scholar 

  17. Doege H, Bocianski A, Joost HG, Schurmann A (2000) Activity and genomic organization of human glucose transporter 9 (GLUT9), a novel member of the family of sugar-transport facilitators predominantly expressed in brain and leucocytes. Biochem J 350:771–776

    CAS  PubMed  Google Scholar 

  18. Doege H, Schurmann A, Bahrenberg G, Brauers A, Joost HG (2000) GLUT8, a novel member of the sugar transport facilitator family with glucose transport activity. J Biol Chem 275:16275–16280

    CAS  PubMed  Google Scholar 

  19. Doege H, Bocianski A, Scheepers A, Axer H, Eckel J, Joost HG, Schurmann A (2001) Characterization of human glucose transporter (GLUT) 11 (encoded by SLC2A11), a novel sugar-transport facilitator specifically expressed in heart and skeletal muscle. Biochem J 359:443–449

    CAS  PubMed  Google Scholar 

  20. Flier JS, Mueckler MM, Usher P, Lodish HF (1987) Elevated levels of glucose transport and transporter messenger RNA are induced by ras or src oncogenes. Science 235:1492–1495

    CAS  PubMed  Google Scholar 

  21. Fukumoto H, Seino S, Imura H, Seino Y, Eddy RL, Fukushima Y, Byers MG, Shows TB, Bell GI (1988) Sequence, tissue distribution, and chromosomal localization of mRNA encoding a human glucose transporter-like protein. Proc Natl Acad Sci USA 85:5434–5438

    CAS  PubMed  Google Scholar 

  22. Fukumoto H, Kayano T, Buse JB, Edwards Y, Pilch PF, Bell GI, Seino S (1989) Cloning and characterization of the major insulin-responsive glucose transporter expressed in human skeletal muscle and other insulin-responsive tissues. J Biol Chem 264:7776–7779

    CAS  PubMed  Google Scholar 

  23. Guillam MT, Hummler E, Schaerer E, Yeh JI, Birnbaum MJ, Beermann F, Schmidt A, Deriaz N, Thorens B, Wu JY (1997) Early diabetes and abnormal postnatal pancreatic islet development in mice lacking Glut-2. Nat Genet 17:327–330

    CAS  PubMed  Google Scholar 

  24. Guillam MT, Burcelin R, Thorens B (1998) Normal hepatic glucose production in the absence of GLUT2 reveals an alternative pathway for glucose release from hepatocytes. Proc Natl Acad Sci USA 95:12317–12321

    CAS  PubMed  Google Scholar 

  25. Guillam MT, Dupraz P, Thorens B (2000) Glucose uptake, utilization, and signaling in GLUT2-null islets. Diabetes 49:1485–1491

    CAS  PubMed  Google Scholar 

  26. Haber RS, Weinstein SP, O’Boyle E, Morgello S (1993) Tissue distribution of the human GLUT3 glucose transporter. Endocrinology 132:2538–2543

    CAS  PubMed  Google Scholar 

  27. Hamill S, Cloherty EK, Carruthers A (1999) The human erythrocyte sugar transporter presents two sugar import sites. Biochemistry 38:16974–16983

    Article  CAS  PubMed  Google Scholar 

  28. Hebert DN, Carruthers A (1992) Glucose transporter oligomeric structure determines transporter function. Reversible redox-dependent interconversions of tetrameric and dimeric GLUT1. J Biol Chem 267:23829–23838

    CAS  PubMed  Google Scholar 

  29. Heijnen HF, Oorschot V, Sixma JJ, Slot JW, James DE (1997) Thrombin stimulates glucose transport in human platelets via the translocation of the glucose transporter GLUT-3 from alpha-granules to the cell surface. J Cell Biol 138:323–330

    Article  CAS  PubMed  Google Scholar 

  30. Holman GD, Kozka IJ, Clark AE, Flower CJ, Saltis J, Habberfield AD, Simpson IA, Cushman SW (1990) Cell surface labeling of glucose transporter isoform GLUT4 by bis-mannose photolabel. Correlation with stimulation of glucose transport in rat adipose cells by insulin and phorbol ester. J Biol Chem 265:18172–18179

    CAS  PubMed  Google Scholar 

  31. Hosokawa M, Thorens B (2002) Glucose release from GLUT2-null hepatocytes: characterization of a major and a minor pathway. Am J Physiol 282:E794–E801

    CAS  Google Scholar 

  32. Ibberson M, Uldry M, Thorens B (2000) GLUTX1, a novel mammalian glucose transporter expressed in the central nervous system and insulin-sensitive tissues. J Biol Chem 275:4607–4612

    CAS  PubMed  Google Scholar 

  33. Ibberson M, Riederer BM, Uldry M, Guhl B, Roth J, Thorens B (2002) Immunolocalization of GLUTX1 in the testis and to specific brain areas and vasopressin-containing neurons. Endocrinology 143:276–284

    CAS  PubMed  Google Scholar 

  34. Johnson JH, Newgard CB, Milburn JL, Lodish HF, Thorens B (1990) The high K m glucose transporter of islets of Langerhans is functionally similar to the low affinity transporter of liver and has an identical primary sequence. J Biol Chem 265:6548–6551

    CAS  PubMed  Google Scholar 

  35. Joost HG, Thorens B (2001) The extended GLUT-family of sugar/polyol transport facilitators: nomenclature, sequence characteristics, and potential function of its novel members (review). Mol Membr Biol 18:247–256

    CAS  PubMed  Google Scholar 

  36. Kaestner KH, Christy RJ, McLenithan JC, Braiterman LT, Cornelius P, Pekala PH, Lane MD (1989) Sequence, tissue distribution, and differential expression of mRNA for a putative insulin-responsive glucose transporter in mouse 3T3-L1 adipocytes. Proc Natl Acad Sci USA 86:3150–3154

    CAS  PubMed  Google Scholar 

  37. Kasahara T, Kasahara M (1996) Expression of the rat GLUT1 glucose transporter in the yeast Saccharomyces cerevisiae. Biochem J 315:177–182

    CAS  PubMed  Google Scholar 

  38. Kasahara T, Kasahara M (1997) Characterization of rat Glut4 glucose transporter expressed in the yeast Saccharomyces cerevisiae: comparison with Glut1 glucose transporter. Biochim Biophys Acta 1324:111–119

    Article  CAS  PubMed  Google Scholar 

  39. Katz EB, Stenbit AE, Hatton K, DePinho R, Charron MJ (1995) Cardiac and adipose tissue abnormalities but not diabetes in mice deficient in GLUT4. Nature 377:151–155

    Google Scholar 

  40. Kayano T, Fukumoto H, Eddy RL, Fan YS, Byers MG, Shows TB, Bell GI (1988) Evidence for a family of human glucose transporter-like proteins. Sequence and gene localization of a protein expressed in fetal skeletal muscle and other tissues. J Biol Chem 263:15245–15248

    CAS  PubMed  Google Scholar 

  41. Kayano T, Burant CF, Fukumoto H, Gould GW, Fan YS, Eddy RL, Byers MG, Shows TB, Seino S, Bell GI (1990) Human facilitative glucose transporters. Isolation, functional characterization, and gene localization of cDNAs encoding an isoform (GLUT5) expressed in small intestine, kidney, muscle, and adipose tissue and an unusual glucose transporter pseudogene-like sequence (GLUT6). J Biol Chem 265:13276–13282

    CAS  PubMed  Google Scholar 

  42. Klepper J, Voit T (2002) Facilitated glucose transporter protein type 1 (GLUT1) deficiency syndrome: impaired glucose transport into brain—a review. Eur J Pediatr 161:295–304

    Article  PubMed  Google Scholar 

  43. Lieb WR, Stein WD (1971) New theory for glucose transport across membranes. Nat New Biol 230:108–109

    CAS  PubMed  Google Scholar 

  44. Macheda ML, Williams ED, Best JD, Wlodek ME, Rogers S (2003) Expression and localisation of GLUT1 and GLUT12 glucose transporters in the pregnant and lactating rat mammary gland. Cell Tissue Res 311:91–97

    Article  CAS  PubMed  Google Scholar 

  45. Maher F, Vannucci SJ, Simpson IA (1994) Glucose transporter proteins in brain. FASEB J 8:1003–1011

    CAS  PubMed  Google Scholar 

  46. Mantych GJ, James DE, Devaskar SU (1993) Jejunal/kidney glucose transporter isoform (Glut-5) is expressed in the human blood-brain barrier. Endocrinology 132:35–40

    CAS  PubMed  Google Scholar 

  47. Mate A, de la Hermosa MA, Barfull A, Planas JM, Vazquez CM (2001) Characterization of D-fructose transport by rat kidney brush-border membrane vesicles: changes in hypertensive rats. Cell Mol Life Sci 58:1961–1967

    CAS  PubMed  Google Scholar 

  48. Matschinsky FM (1996) Banting Lecture 1995. A lesson in metabolic regulation inspired by the glucokinase glucose sensor paradigm. Diabetes 45:223–241

    CAS  PubMed  Google Scholar 

  49. McVie-Wylie AJ, Lamson DR, Chen YT (2001) Molecular cloning of a novel member of the GLUT family of transporters, SLC2a10 (GLUT10), localized on chromosome 20q13.1: a candidate gene for NIDDM susceptibility. Genomics 72:113–117

    Article  CAS  PubMed  Google Scholar 

  50. Miyamoto K, Tatsumi S, Morimoto A, Minami H, Yamamoto H, Sone K, Taketani Y, Nakabou Y, Oka T, Takeda E (1994) Characterization of the rabbit intestinal fructose transporter (GLUT5). Biochem J 303:877–883

    CAS  PubMed  Google Scholar 

  51. Morris DI, Robbins JD, Ruoho AE, Sutkowski EM, Seamon KB (1991) Forskolin photoaffinity labels with specificity for adenylyl cyclase and the glucose transporter. J Biol Chem 266:13377–13384

    CAS  PubMed  Google Scholar 

  52. Mueckler M, Makepeace C (2002) Analysis of transmembrane segment 10 of the Glut1 glucose transporter by cysteine-scanning mutagenesis and substituted cysteine accessibility. J Biol Chem 277:3498–3503

    Article  CAS  PubMed  Google Scholar 

  53. Mueckler M, Caruso C, Baldwin SA, Panico M, Blench I, Morris HR, Allard WJ, Lienhard GE, Lodish HF (1985) Sequence and structure of a human glucose transporter. Science 229:941–945

    CAS  PubMed  Google Scholar 

  54. Mueckler M, Weng W, Kruse M (1994) Glutamine 161 of Glut1 glucose transporter is critical for transport activity and exofacial ligand binding. J Biol Chem 269:20533–20538

    CAS  PubMed  Google Scholar 

  55. Murata H, Hruz PW, Mueckler M (2002) Indinavir inhibits the glucose transporter isoform Glut4 at physiologic concentrations. Aids 16:859–863

    Article  CAS  PubMed  Google Scholar 

  56. Nelson JA, Falk RE (1993) Phloridzin and phloretin inhibition of 2-deoxy-d-glucose uptake by tumor cells in vitro and in vivo. Anticancer Res 13:2293–2299

    CAS  PubMed  Google Scholar 

  57. Pellerin L, Bonvento G, Chatton JY, Pierre K, Magistretti PJ (2002) Role of neuron-glia interaction in the regulation of brain glucose utilization. Diabetes Nutr Metab 15:268–273; discussion 273

    CAS  PubMed  Google Scholar 

  58. Phay JE, Hussain HB, Moley JF (2000) Cloning and expression analysis of a novel member of the facilitative glucose transporter family, SLC2A9 (GLUT9). Genomics 66:217–220

    Article  CAS  PubMed  Google Scholar 

  59. Pinto AB, Carayannopoulos MO, Hoehn A, Dowd L, Moley KH (2002) Glucose transporter 8 expression and translocation are critical for murine blastocyst survival. Biol Reprod 66:1729–1733

    CAS  PubMed  Google Scholar 

  60. Rand EB, Depaoli AM, Davidson NO, Bell GI, Burant CF (1993) Sequence, tissue distribution, and functional characterization of the rat fructose transporter GLUT5. Am J Physiol 264:G1169–1176

    CAS  PubMed  Google Scholar 

  61. Rogers S, Macheda ML, Docherty SE, Carty MD, Henderson MA, Soeller WC, Gibbs EM, James DE, Best JD (2002) Identification of a novel glucose transporter-like protein-GLUT-12. Am J Physiol 282:E733–E738

    CAS  Google Scholar 

  62. Saltiel AR, Pessin JE (2002) Insulin signaling pathways in time and space. Trends Cell Biol 12:65–71

    Article  CAS  PubMed  Google Scholar 

  63. Santer R, Groth S, Kinner M, Dombrowski A, Berry GT, Brodehl J, Leonard JV, Moses S, Norgren S, Skovby F, Schneppenheim R, Steinmann B, Schaub J (2002) The mutation spectrum of the facilitative glucose transporter gene SLC2A2 (GLUT2) in patients with Fanconi-Bickel syndrome. Hum Genet 110:21–29

    Article  CAS  PubMed  Google Scholar 

  64. Sasaki T, Minoshima S, Shiohama A, Shintani A, Shimizu A, Asakawa S, Kawasaki K, Shimizu N (2001) Molecular cloning of a member of the facilitative glucose transporter gene family GLUT11 (SLC2A11) and identification of transcription variants. Biochem Biophys Res Commun 289:1218–1224

    Article  CAS  PubMed  Google Scholar 

  65. Schurmann A, Axer H, Scheepers A, Doege H, Joost HG (2002) The glucose transport facilitator GLUT8 is predominantly associated with the acrosomal region of mature spermatozoa. Cell Tissue Res 307:237–242

    Article  PubMed  Google Scholar 

  66. Seatter MJ, De la Rue SA, Porter LM, Gould GW (1998) QLS motif in transmembrane helix VII of the glucose transporter family interacts with the C-1 position ofd-glucose and is involved in substrate selection at the exofacial binding site. Biochemistry 37:1322–1326

    Article  CAS  PubMed  Google Scholar 

  67. Seidner G, Alvarez MG, Yeh JI, O’Driscoll KR, Klepper J, Stump TS, Wang D, Spinner NB, Birnbaum MJ, De Vivo DC (1998) GLUT-1 deficiency syndrome caused by haploinsufficiency of the blood-brain barrier hexose carrier. Nat Genet 18:188–191

    CAS  PubMed  Google Scholar 

  68. Stenbit AE, Tsao TS, Li J, Burcelin R, Geenen DL, Factor SM, Houseknecht K, Katz EB, Charron MJ (1997) GLUT4 heterozygous knockout mice develop muscle insulin resistance and diabetes. Nat Med 3:1096–1101

    CAS  PubMed  Google Scholar 

  69. Stuart CA, Wen G, Jiang J (1999) GLUT3 protein and mRNA in autopsy muscle specimens. Metabolism 48:876–880

    CAS  PubMed  Google Scholar 

  70. Stumpel F, Burcelin R, Jungermann K, Thorens B (2001) Normal kinetics of intestinal glucose absorption in the absence of GLUT2: evidence for a transport pathway requiring glucose phosphorylation and transfer into the endoplasmic reticulum. Proc Natl Acad Sci USA 98:11330–11335

    Article  CAS  PubMed  Google Scholar 

  71. Thoidis G, Kupriyanova T, Cunningham JM, Chen P, Cadel S, Foulon T, Cohen P, Fine RE, Kandror KV (1999) Glucose transporter Glut3 is targeted to secretory vesicles in neurons and PC12 cells. J Biol Chem 274:14062–14066

    Article  CAS  PubMed  Google Scholar 

  72. Thorens B, Sarkar HK, Kaback HR, Lodish HF (1988) Cloning and functional expression in bacteria of a novel glucose transporter present in liver, intestine, kidney, and beta-pancreatic islet cells. Cell 55:281–290

    CAS  PubMed  Google Scholar 

  73. Thorens B, Cheng ZQ, Brown D, Lodish HF (1990) Liver glucose transporter: a basolateral protein in hepatocytes and intestine and kidney cells. Am J Physiol 259:C279–C285

    CAS  PubMed  Google Scholar 

  74. Uldry M, Ibberson M, Horisberger JD, Chatton JY, Riederer BM, Thorens B (2001) Identification of a mammalian H+-myo-inositol symporter expressed predominantly in the brain. EMBO J 20:4467–4477

    CAS  PubMed  Google Scholar 

  75. Uldry M, Ibberson M, Hosokawa M, Thorens B (2002) GLUT2 is a high affinity glucosamine transporter. FEBS Lett 524:199–203

    Article  CAS  PubMed  Google Scholar 

  76. Wright EM, Turk E (2003) The sodium glucose cotransporter family SLC5. Pflugers Archives, in press (this issue)

  77. Wu X, Li W, Sharma V, Godzik A, Freeze HH (2002) Cloning and characterization of glucose transporter 11, a novel sugar transporter that is alternatively spliced in various tissues. Mol Genet Metab 76:37–45

    Article  CAS  PubMed  Google Scholar 

  78. Zisman A, Peroni OD, Abel ED, Michael MD, Mauvais-Jarvis F, Lowell BB, Wojtaszewski JF, Hirshman MF, Virkamaki A, Goodyear LJ, Kahn CR, Kahn BB (2000) Targeted disruption of the glucose transporter 4 selectively in muscle causes insulin resistance and glucose intolerance. Nat Med 6:924–928

    CAS  PubMed  Google Scholar 

  79. Zuniga FA, Shi G, Haller JF, Rubashkin A, Flynn DR, Iserovich P, Fischbarg J (2001) A three-dimensional model of the human facilitative glucose transporter Glut1. J Biol Chem 276:44970–44975

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Bernard Thorens.

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An erratum to this article can be found at http://dx.doi.org/10.1007/s00424-004-1264-7

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Uldry, M., Thorens, B. The SLC2 family of facilitated hexose and polyol transporters. Pflugers Arch - Eur J Physiol 447, 480–489 (2004). https://doi.org/10.1007/s00424-003-1085-0

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