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Autor     Marc Uldry, Bernard Thorens
Titel    The SLC2 family of facilitated hexose and polyol transporters
Zeitschrift    Pflugers Arch - Eur J Physiol
Ausgabe    447
Jahr    2004
Nummer    5
Seiten    480-489
URL    http://link.springer.com/article/10.1007/s00424-003-1085-0?no-access=true

Literaturverz.   

no
Fußnoten    no
Fragmente    6


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Facilitated diffusion of glucose and related hexoses across biological membranes is catalysed by members of the SLC2 family, referred to as glucose transporters or GLUTs. These transporters function as simple carriers and the movement of hexose across the plasma membrane proceeds in the direction imposed by its electrochemical gradient. A common structural feature of the SLC2 family members is the presence of 12 transmembrane domains (TM) with both the amino and carboxy-terminal ends present on the cytosolic side and a unique N-linked oligosaccharide side-chain present either in the first or the fourth extracellular loop (16).

16. Mueckler,M, Makepeace,C: Transmembrane segment 12 of the Glut1 glucose transporter is an outer helix and is not directly involved in the transport mechanism. J.Biol.Chem. 281:36993-36998, 2006

Facilitated diffusion of glucose and related hexoses across biological membranes is catalysed by members of the SLC2 family, referred to as glucose transporters or GLUTs. These transporters function as simple carriers and the movement of hexose across the plasma membrane proceeds in the direction imposed by its electrochemical gradient. A common structural feature of the SLC2 family member is the presence of 12 transmembrane domains (TM) with both the amino and carboxy-terminal ends present on the cytosolic side and a unique N-linked oligosaccharide side-chain present either in the first or the fourth extracellular loop.
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[Signature sequences conserved between the] different members of the SLC2 family are present at distinct locations in the primary structure. The presence of these sequences, however, does not predict the substrate specificity of these transporters.

Glucose transporters are expressed in every cell of the body, as might be anticipated from the key role of glucose in providing metabolic energy and building blocks for the synthesis of biomolecules. The specific physiological role of the isoforms expressed in tissues involved in the control of glucose homeostasis, i.e. muscle, adipose tissue, liver, pancreatic beta-cells and brain, has been studied in greatest detail. Indeed, in these tissues glucose transporters play important roles in the control of glucose utilization, glucose production and glucose sensing and their dysregulated expression may underlie pathogenetic mechanisms leading to development of diabetes mellitus, but also other specific monogenic diseases (17).

Facilitated diffusion of glucose across plasma membranes has been studied for several decades (18). The recognition that human erythrocytes have a high density of glucose transporters allowed the initial biochemical purification of this transporter and the preparation of specific antibodies. These were then used for initial cloning of a human glucose transporter by screening an expression library prepared from a human hepatoma cell line (HepG2) (4).This glucose transporter, named GLUT1 (SLC2A1) , was then used for subsequent cloning, by low-stringency screening, of GLUT2–5 (SLC2A2, SLC2A3, SLC2A4, SLC2A5)


4. Kloppel,G, Lohr,M, Habich,K, Oberholzer,M, Heitz,PU: Islet pathology and the pathogenesis of type 1 and type 2 diabetes mellitus revisited. Surv.Synth.Pathol.Res. 4:110-125, 1985

17. Fernandez,EB: [Monogenic forms of diabetes mellitus]. An.R.Acad.Nac.Med.(Madr.) 123:211-217, 2006

18. Gylfe,E, Grapengiesser,E, Hellman,B: Propagation of cytoplasmic Ca2+ oscillations in clusters of pancreatic beta-cells exposed to glucose. Cell Calcium 12:229-240, 1991

Signature sequences conserved between the different members of the SLC2 family are present at distinct locations in the primary structure (Fig. 2). The presence of these sequences, however, does not predict the substrate specificity of these transporters.

Glucose transporters are expressed in every cell of the body, as might be anticipated from the key role of glucose in providing metabolic energy and building blocks for the synthesis of biomolecules. The specific physiological role of the isoforms expressed in tissues involved in the control of glucose homeostasis, i.e. muscle, adipose tissue, liver, pancreatic beta- cells and brain, has been studied in greatest detail. Indeed, in these tissues glucose transporters play important roles in the control of glucose utilization, glucose production and glucose sensing and their dysregulated expression may underlie pathogenetic mechanisms leading to development of diabetes mellitus, but also other specific monogenic diseases (see below).

Facilitated diffusion of glucose across plasma membranes has been studied for several decades [43]. The recognition that human erythrocytes have a high density of glucose transporters allowed the initial biochemical purification of this transporter and the preparation of specific antibodies. These were then used for initial cloning of a human glucose transporter by screening an expression library prepared from a human hepatoma cell line (HepG2) [53]. This glucose transporter, GLUT1, was then used for subsequent cloning, by low-stringency screening, of GLUT2–5.


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

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

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1.3.1 The facilitative glucose transporters in the CNS and blood brain barrier

Glucose is the preferred energy substrate of the brain. Due to its expression in the endothelial cells forming the blood brain barrier, the glucose transporter GLUT1 is essential for glucose delivery to the brain (22).Given the fact that the abluminal surface of brain capillaries is covered by specialized astrocytic end-feet that also express GLUT1, the astrocytes probably constitute a major site of glucose uptake (23) In astrocytes, glucose is catabolized by glycolysis to lactate, which may be delivered to neurons through a glialspecific monocarboxylate transporter (MCT1) and a neuron-specific one (MCT2). In neurons, lactate is converted to pyruvate, which enters the tricarboxylic acid cycle to generate ATP. Glucose can also be taken up directly by neurons, which express the GLUT3 isoform (24). GLUT2 is also expressed in the brain in specific regions such as the hypothalamus and the brain stem where it may participate in the mechanisms of glucose sensing involved in the control of glucose homeostasis.

The role of GLUT8 in some specific neurons remains unclear. It is localized to intracellular vesicles and may possibly move to the cell surface upon as yet unidentified stimuli (25) . Finally, HMIT is expressed in astrocytes and in neurons. In astrocytes, HMIT is both intracellular and at the plasma membrane, whereas its subcellular localization in neurons is under investigation (26).

1.3.2 The facilitative glucose transporters as pharmaceutical targets

Elevation of blood glucose is the main symptom of types 1 and 2 diabetes. The GLUT isoforms that transport glucose represent therefore a potential therapeutic target for normalizing glycaemia. A compound that increases the Vmax maximal velocity of GLUT1 would increase whole-body glucose utilization. Given the fact that this isoform is almost ubiquitous, such activation could, however, also lead to severe hypoglycaemia. Another possible site of action for limiting the blood glucose level would be inhibition of glucose absorption in the intestine or reabsorption in the kidney. In the intestine, this could be possible by blocking both GLUT2 and the alternative membrane-traffic-based pathway of basolateral glucose release. In the kidney, GLUT2 deficiency results in glucose excretion in the urine, which decreases glycaemia (27). Inhibition of GLUT2 specifically in the kidney could thus treat hyperglycaemia.


22. Klepper,J, Scheffer,H, Leiendecker,B, Gertsen,E, Binder,S, Leferink,M, Hertzberg,C, Nake,A, Voit,T, Willemsen,MA: Seizure control and acceptance of the ketogenic diet in GLUT1 deficiency syndrome: a 2- to 5-year follow-up of 15 children enrolled prospectively. Neuropediatrics 36:302-308, 2005

23. Belanger,M, Desjardins,P, Chatauret,N, Butterworth,RF: Selectively increased expression of the astrocytic/endothelial glucose transporter protein GLUT1 in acute liver failure. Glia 53:557-562, 2006

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

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

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

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

GLUTs in the CNS and blood brain barrier

Glucose is the preferred energy substrate of the brain. Due to its expression in the endothelial cells forming the blood brain barrier, GLUT1 is essential for glucose delivery to the brain. Given the fact that the abluminal surface of brain capillaries is covered by specialized astrocytic end-feet that also express GLUT1, the astrocytes probably constitute a major site of glucose uptake. In astrocytes, glucose is catabolized by glycolysis to lactate, which may be delivered to neurons through a glial-specific monocarboxylate transporter (MCT1) and a neuron-specific one (MCT2). In neurons, lactate is converted to pyruvate, which enters the tricarboxylic acid cycle to generate ATP. Glucose can also be taken up directly by neurons, which express the GLUT3 isoform [57]. GLUT2 is also expressed in the brain in specific regions such as the hypothalamus and the brain stem where it may participate in the mechanisms of glucose sensing involved in the control of glucose homeostasis.

The role of GLUT8 in some specific neurons remains unclear. It is localized to intracellular vesicles and may possibly move to the cell surface upon as yet unidentified stimuli [33]. Finally, HMIT is expressed in astrocytes and in neurons. In astrocytes, HMIT is both intracellular and at the plasma membrane, whereas its subcellular localization in neurons is under investigation [74].

Pharmaceutical relevance

Elevation of blood glucose is the main symptom of types-1 or -2 diabetes. The GLUT isoforms that transport glucose represent therefore a potential therapeutic target for normalizing glycaemia. A compound that increases the Vmax of GLUT1 would increase whole-body glucose utilization. Given the fact that this isoform is almost ubiquitous, such activation could, however, also lead to severe hypoglycaemia. Another possible site of action for limiting the blood glucose level would be inhibition of glucose absorption in the intestine or reabsorption in the kidney. In the intestine, this could be possible by blocking both GLUT2 and the alternative membrane-traffic-based pathway of basolateral glucose release. In the kidney, GLUT2 deficiency results in glucose excretion in the urine, which decreases glycaemia [23]. Inhibition of GLUT2 specifically in the kidney could thus treat hyperglycaemia.


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

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

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

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

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[However, the sodium dependent glucose transporter] SGLT2 (SLC5A1) seems to be a more interesting target in the kidney for this purpose since its expression is more limited.

Type 2 diabetes is characterized by the loss of insulin sensitivity that leads to a decrease in GLUT1 translocation to the plasma membrane in response to a high blood glucose. To compensate the resulting reduced flux of glucose into muscle and adipocytes, it would be useful to find a pharmacological compound that increases the Vmax of GLUT1 for glucose, or stimulate its translocation to the cell surface.

An impaired brain inositol metabolism has been linked to psychiatric diseases, in particular bipolar disorders (28). Indeed, current treatments of these mood disorders relies on the use of Li+ salts, valproic acid and carbamazepine, drugs whose action may interfere with inositol metabolism.(28) It is well established that one mechanism of action of Li+ is the inhibition of inositol monophosphate phosphatase and polyphosphoinositide 1-phosphate phosphatase (29), which blocks recycling of inositol phosphate and reduces the availability of inositol for subsequent cycles of intracellular signal transduction. Inhibition of HMIT could also lead to such beneficial effects for bipolar disorders by decreasing the intracellular inositol concentration.

Some members of the GLUT family (GLUT1, 2 and 4) can transport glucosamine, which is important in the biosynthesis of glycoproteins and, in particular, glycosaminoglycan synthesis in cartilage (30). In association with collagen fibres, these molecules are responsible for the resilience of the cartilage to deformation. Destruction of joint cartilage occurs in osteoarthritis, and several studies have shown that glucosamine is beneficial for this disease . Given the fact that GLUT1 is expressed in chondrocytes, the cells that synthesize cartilage, glucosamine has favourable effects for osteoarthritis are probably mediated by transport across GLUT1 into these cells. Furthermore, glucosamine absorption seems to be mediated in part by GLUT2. This provides an example of the use of GLUT isoforms to deliver therapeutic molecules to their site of action.

1.3.3 The facilitative glucose transporter GLUT1

GLUT1 cDNA was isolated from an expression library using antibodies against the human´s erythrocyte glucose transporter(4). Although cloned from a hepatoma cDNA library, GLUT1 is not expressed in normal hepatocytes. It is, however, induced during oncogenic transformation of most cell types and its expression correlates with the increase in glucose [metabolism observed in tumour cells (31).]


4. Kloppel,G, Lohr,M, Habich,K, Oberholzer,M, Heitz,PU: Islet pathology and the pathogenesis of type 1 and type 2 diabetes mellitus revisited. Surv.Synth.Pathol.Res. 4:110-125, 1985

28. Shaldubina,A, Buccafusca,R, Johanson,RA, Agam,G, Belmaker,RH, Berry,GT, Bersudsky,Y: Behavioural phenotyping of sodium-myo-inositol cotransporter heterozygous knockout mice with reduced brain inositol. Genes Brain Behav. 6:253-259, 2007

29. Berridge,MJ, Downes,CP, Hanley,MR: Neural and developmental actions of lithium: a unifying hypothesis. Cell 59:411-419, 1989

30. Uldry,M, Ibberson,M, Hosokawa,M, Thorens,B: GLUT2 is a high affinity glucosamine transporter. FEBS Lett. 524:199-203, 2002

31. Haber,PS, Pirola,RC, Wilson,JS: Clinical update: management of acute pancreatitis. J.Gastroenterol.Hepatol. 12:189-197, 1997

[page 481]

GLUT1

Glut 1 was the first transporter to be characterized by molecular cloning, and its cDNA was isolated from an expression library using antibodies against the humans erythrocyte glucose transporter [53]. Although cloned from a hepatoma cDNA library, GLUT1 is not expressed in normal hepatocytes. It is, however, induced during oncogenic transformation of most cell types and its expression correlates with the increase in glucose metabolism observed in tumour cells [20].

[page 487]

However, SGLT2 seems to be a more interesting target in the kidney for this purpose since its expression is more limited.

Type-2 diabetes is characterized by the loss of insulin sensitivity that leads to a decrease in GLUT4 translocation to the plasma membrane in response to a high blood glucose. To compensate the resulting reduced flux of glucose into muscle or adipocytes, it would be useful to find a pharmacological compound that increases the Vmax of GLUT4 for glucose, or stimulate its translocation to the cell surface.

An impaired brain inositol metabolism has been linked to psychiatric diseases, in particular bipolar disorders. Indeed, current treatments of these mood disorders relies on the use of lithium salts, valproic acid and carbamazepine, drugs whose action may interfere with inositol metabolism. It is well established that one mechanism of action of Li+ is the inhibition of inositol monophosphate phosphatase and polyphosphoinositide 1-phosphate phosphatase [6], which blocks recycling of inositol phosphate and reduces the availability of inositol for subsequent cycles of intracellular signal transduction. Inhibition of HMIT could also lead to such beneficial effects for bipolar disorders by decreasing the intracellular inositol concentration.

Some members of the GLUT family (GLUT1, 2 and 4) can transport glucosamine, which is important in the biosynthesis of glycoproteins and, in particular, glycosaminoglycan synthesis in cartilage [75]. In association with collagen fibres, these molecules are responsible for the resilience of the cartilage to deformation. Destruction of joint cartilage occurs in osteoarthritis, and several studies have shown that glucosamine is beneficial for this disease. Given the fact that GLUT1 is expressed in chondrocytes, the cells that synthesize cartilage, glucosamine’s favourable effects for osteoarthritis are probably mediated by transport across GLUT1 into these cells. Furthermore, glucosamine absorption seems to be mediated in part by GLUT2. This provides an example of the use of GLUT isoforms to deliver therapeutic molecules to their site of action.


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

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

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

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

Anmerkungen

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GLUT1 is found in almost every tissue with different levels of expression in different cell types. The expression level usually correlates with the rate of cellular glucose metabolism. As mentioned above, it is also expressed highly in blood-tissue barriers, in particular in the endothelial cells forming the blood-brain barrier. Several heterozygous mutations resulting in GLUT1 haploinsufficiency have been identified. These cause hypoglycorrachia, a condition characterized by seizures, developmental delay, acquired microcephaly, and hypotonia, and which is due to a decrease rate of glucose transport from the blood into cerebrospinal fluid.

The topological arrangement of GLUT1 within the plasma membrane has been confirmed using several experimental approaches. Recently, two models have been proposed for the tertiary structure of GLUT1. The first is based on data obtained from cysteine scanning mutagenesis of five of the α-helices of GLUT1 together with information from site-directed mutagenesis (32). The second is based primarily on the proposed helical bundle arrangement of the Lac permease and has been refined using energy minimization algorithm (33) These two models describe a key role for helix 7 in the formation of a water-filled channel which may form the path for glucose across the plasma membrane.

The transport of glucose may be described as an alternating confirmation model in which the transporter has mutually exclusive binding sites located on the extracellular (import site) and on the intracellular face (export site) of the transporter (Figure 4). Binding of glucose to one site induces the transporter to switch to the opposite conformation, a process that is accompanied by a movement of the substrate across the plasma membrane (34). In human erythrocytes, GLUT1 is thought to be present as homodimers or homotetramers, with the conversion between both oligomeric forms being dependent on the redox state, . GLUT1 transports glucose with an affinity constant (Km) of ~3 mM. Other transported substrates are galactose (30mM) (34), mannose (35) (20mM) and glucosamine 2.1±0.5mM (36). Glucose transport by GLUT1 is sensitive to several inhibitors that also block transport by other isoforms. Many of them are competitive inhibitors of sugar binding, either to the extracellular or the cytosolic sugar binding sites. Cytochalasin B binds to the inner surface of GLUT1 and inhibits its glucose transport activity with an IC50 of 0.44 μM. Binding of cytochalasin B is to a site which contains tryptophan 388 and 412. Also acting on the same intracellular site is the diterpene toxin forskolin. Forskolin has been used as a photoaffinity label with some specificity for the glucose transporter and its affinity is increased in the 3-iodo4-azidophenethylamido-7-O-succinyldeacetyl (IAPS) derivative.


32. Keymeulen,B, Ling,Z, Gorus,FK, Delvaux,G, Bouwens,L, Grupping,A, Hendrieckx,C, Pipeleers-Marichal,M, Van Schravendijk,C, Salmela,K, Pipeleers,DG: Implantation of standardized beta-cell grafts in a liver segment of IDDM patients: graft and recipients characteristics in two cases of insulin-independence under maintenance immunosuppression for prior kidney graft. Diabetologia 41:452-459, 1998

33. Fischbarg,J, Cheung,M, Li,J, Iserovich,P, Czegledy,F, Kuang,K, Garner,M: Are most transporters and channels beta barrels? Mol.Cell Biochem. 140:147-162, 1994

34. Joost,HG, Thorens,B: 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, 2001

35. Palfreyman,RW, Clark,AE, Denton,RM, Holman,GD, Kozka,IJ: Kinetic resolution of the separate GLUT1 and GLUT4 glucose transport activities in 3T3-L1 cells. Biochem.J. 284 ( Pt 1):275-282, 1992

36. Robinson,KA, Sens,DA, Buse,MG: Pre-exposure to glucosamine induces insulin resistance of glucose transport and glycogen synthesis in isolated rat skeletal muscles. Study of mechanisms in muscle and in rat-1 fibroblasts overexpressing the human insulin receptor. Diabetes 42:1333-1346, 1993

[page 481]

GLUT1 is found in almost every tissue with different levels of expression in different cell types. The expression level usually correlates with the rate of cellular glucose metabolism. It is also expressed highly in blood-tissue barriers, in particular in the endothelial cells forming the blood-brain barrier [45].

The topological arrangement of GLUT1 within the plasma membrane has been confirmed using several experimental approaches. Recently, two models have been proposed for the tertiary structure of GLUT1. The first is based on data obtained from cysteine scanning mutagenesis of five of the α-helices of GLUT1 together with information from site-directed mutagenesis [52]. The second is based primarily on the proposed helical bundle arrangement of the Lac permease and has been refined using energy minimization algorithm [79]. These two models describe a key role for helix 7 in the formation of a water-filled channel which may form the path for glucose across the plasma membrane.

The transport of glucose may be described as an alternating conformer model in which the transporter has mutually exclusive binding sites located on the extracellular (import site) and on the intracellular face (export site) of the transporter. Binding of glucose to one site induces the transporter to switch to the opposite conformation, a process that is accompanied by a movement of the substrate across the plasma membrane. In human erythrocytes, GLUT1 is thought to be present as homodimers or homotetramers, with the conversion between both oligomeric forms being dependent on the redox state [27, 28]. GLUT1 transports glucose with a Km of ~3 mM. Other transported substrates are galactose, mannose and glucosamine [75].

Glucose transport by GLUT1 is sensitive to several inhibitors that also block transport by other isoforms. Many of them are competitive inhibitors of sugar binding, either to the extracellular or the cytosolic sugar binding sites. Cytochalasin B binds to the inner surface of GLUT1 [4] and inhibits its glucose transport activity with an IC50 of 0.44 μM. Binding of cytochalasin B is to a site which contains tryptophan 388 and 412 (see Fig. 2). Also acting on the same intracellular site is the diterpene toxin forskolin. Forskolin has been used as a photoaffinity label with some specificity for the glucose transporter and its affinity is increased in the 3-iodo4-azidophenethylamido-7-O-succinyldeacetyl (IAPS) derivative. [...]

[...]

Several heterozygous mutations resulting in GLUT1 haploinsufficiency have been identified. These cause

[page 482]

hypoglycorrachia, a condition characterized by seizures, developmental delay, acquired microcephaly, and hypotonia, and which is due to a decrease rate of glucose transport from the blood into cerebrospinal fluid [42, 67].


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

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

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

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

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

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

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

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

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

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[An iodinated derivative] of forskolin (7-aminoalkylcarbamate) with a very high affinity (IC50 200 nM) has also been described (37).

Glucose transport activity of GLUT1 is inhibited by HgCl2 (IC50 3.5 μM), phloretin (IC50 49 μM), phlorizin (IC50 355 μM) and 4,6-O-ethylidene-D-glucose (IC50 12 mM), which bind to the external glucose binding site where glutamine 161 appears to be critical for inhibitor binding (16).


16. Mueckler,M, Makepeace,C: Transmembrane segment 12 of the Glut1 glucose transporter is an outer helix and is not directly involved in the transport mechanism. J.Biol.Chem. 281:36993-36998, 2006

37. Harrison,SA, Buxton,JM, Czech,MP: Suppressed intrinsic catalytic activity of GLUT1 glucose transporters in insulin-sensitive 3T3-L1 adipocytes. Proc.Natl.Acad.Sci.U.S.A 88:7839-7843, 1991

An iodinated derivative of forskolin (7-aminoalkylcarbamate) with a very high affinity (IC50 200 nM) has also been described [51].

Glucose transport activity of GLUT1 is inhibited by HgCl2 (IC50 3.5 μM), phloretin (IC50 49 μM) phlorizin (IC50 355 μM) [37] and 4,6-O-ethylidene-d-glucose (IC50 12 mM), which binds to the external glucose binding site where glutamine 161 appears to be critical for inhibitor binding [54]


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

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

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

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