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Quelle: McCarthy and Elmendorf 2007 Seite(n): 380, 381, Zeilen: 380: l.col: 27ff; 381: l.col: 14ff |
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| 1.3.8 Role of SNARE proteins in GLUT4 regulation
After the insulin-mediated arrival of GLUT4-containing vesicles from intracellular storage sites to the plasma membrane, regulated fusion of these vesicles ensues. Exocytosis of GLUT4-containing vesicles is mediated by interactions between specific vesicular and plasma membrane protein complexes known as SNAREs. Vesicle SNAREs (v-SNARES, vesicle soluble N-ethylmaleimide-sensitive factor attachment protein receptors) bind target membrane SNAREs (t-SNAREs) in company with numerous accessory proteins. Syntaxin4 and SNAP23 (23 kDa synaptosomal-associated protein) are the t-SNARES and VAMP2 is the v-SNARE involved in GLUT4 vesicle fusion (67) While SNAREs are essential in GLUT4 exocytosis, they themselves do not appear to be the direct targets of insulin action. Rather, studies suggest that the accessory proteins Munc18 and Synip may be regulated by insulin to accomplish fusion events. Three Munc18 isoforms (Munc18ac) have been identified in mammalian cells: Munc18a (67) is a neuronal isoform and Munc18b and Munc18c are expressed in muscle and adipose tissues. In addition to Munc18, the accessory protein Synip may also play a role in insulin stimulated GLUT4 vesicle fusion (68), although data are conflicting. Synip was first identified by Min and colleagues, who determined that this protein dissociates from syntaxin4 in an insulin-dependent manner and is directly involved in GLUT4 translocation. Recently, it was reported that Akt2 phosphorylates Synip on serine 99 and this phosphorylation mediates the Synip-syntaxin4 dissociation necessary for GLUT4 vesicle exocytosis (69). However, recent studies argue against this possibility and show that a serine-to-alanine Synip mutant (S99A) does not impair GLUT4 translocation. 1.3.9 Role of GLUT4 dysfunctions in obesity and type 2 diabetes Insulin resistance is significantly caused by both genetic and environmental components. Mutations in the insulin receptor are rare but result in extremely severe insulin resistance. These include Leprechaunism, Rabson-Mendenhall Syndrome, and the type A syndrome of insulin resistance (70). Type 2 diabetes is polygenic, probably involving defects at numerous points in the glucose regulatory system. For example, skeletal muscle analyzed from type 2 diabetic subjects displays diminished insulin-stimulated IRS-1 tyrosine phosphorylation and decreased PI3K activity coupled to impaired glucose transport. These defects could not be explained by alterations in protein expression. Likewise, skeletal muscle and adipocytes from obese, Type 2 diabetic patients demonstrate impaired insulin-triggered IRS-1 associated [PI3K activity (71), (44).] 44. Bjornholm,M, Zierath,JR: Insulin signal transduction in human skeletal muscle: identifying the defects in Type II diabetes. Biochem.Soc.Trans. 33:354-357, 2005 67. Thurmond,DC, Pessin,JE: Molecular machinery involved in the insulin-regulated fusion of GLUT4-containing vesicles with the plasma membrane (review). Mol.Membr.Biol. 18:237-245, 2001 68. Min,J, Okada,S, Kanzaki,M, Elmendorf,JS, Coker,KJ, Ceresa,BP, Syu,LJ, Noda,Y, Saltiel,AR, Pessin,JE: Synip: a novel insulin-regulated syntaxin 4-binding protein mediating GLUT4 translocation in adipocytes. Mol.Cell 3:751-760, 1999 69. Yamada,E, Okada,S, Saito,T, Ohshima,K, Sato,M, Tsuchiya,T, Uehara,Y, Shimizu,H, Mori,M: Akt2 phosphorylates Synip to regulate docking and fusion of GLUT4- containing vesicles. J.Cell Biol. 168:921-928, 2005 70. Saltiel,AR, Kahn,CR: Insulin signalling and the regulation of glucose and lipid metabolism. Nature 414:799-806, 2001 71. Krook,A, Bjornholm,M, Galuska,D, Jiang,XJ, Fahlman,R, Myers,MG, Jr., Wallberg- Henriksson,H, Zierath,JR: Characterization of signal transduction and glucose transport in skeletal muscle from type 2 diabetic patients. Diabetes 49:284-292, 2000 |
SNAREing GLUT4
Following the insulin-mediated arrival of GLUT4-containing vesicles from intracellular storage sites to the plasma membrane, regulated fusion of these vesicles ensues. Exocytosis of GLUT4-containing vesicles is mediated by interactions between specific vesicular and plasma membrane protein complexes known as SNAREs (Fig. C). Vesicle SNAREs (v-SNARES, vesicle soluble N-ethylmaleimide-sensitive factor attachment protein receptors) bind target membrane SNAREs (t-SNAREs) in company with numerous accessory proteins. Syntaxin4 and SNAP23 (23 kDa synaptosomal-associated protein) are the t-SNARES and VAMP2 is the v-SNARE involved in GLUT4 vesicle fusion106. While SNAREs are essential in GLUT4 exocytosis, they themselves do not appear to be direct targets of insulin action. Rather, studies suggest that the accessory proteins Munc18 and Synip may be regulated by insulin to accomplish fusion events. Three Munc18 isoforms (Munc18ac) have been identified in mammalian cells: Munc18a is a neuronal isoform and Munc18b and Munc18c are expressed in muscle and fat. [...] In addition to Munc18c, the accessory protein Synip may also play a role in insulin-stimulated GLUT4 vesicle fusion, although data are conflicting. Synip was first identified by Min and colleagues112, who determined that this protein dissociates from syntaxin4 in an insulin-dependent manner and is directly involved in GLUT4 translocation. Recently, it was reported that Akt2 phosphorylates Synip on serine 99 and this phosphorylation mediates the Synip-syntaxin4 dissociation necessary for GLUT4 vesicle exocytosis113. However, recent studies argue against this possibility and show that a serine-to-alanine Synip mutant (S99A) does not impair GLUT4 translocation114. [page 381] [...] GLUT4 dysregulation in obesity and type 2 diabetes Abundant studies of insulin resistance demonstrate defects at numerous levels in the insulin-regulated glucose transport pathway. Insulin sensitivity is profoundly affected by both genetic and environmental components. Mutations in the insulin receptor are rare but result in extremely severe insulin resistance. These include Leprechaunism, Rabson-Mendenhall Syndrome, and the type A syndrome of insulin resistance117. Type 2 diabetes is polygenic, probably involving defects at numerous points in the glucose regulation system. For example, skeletal muscle analyzed from type 2 diabetic subjects versus lean controls displays diminished insulin-stimulated IRS-1 tyrosine phosphorylation and decreased PI3K activity coupled to impaired glucose transport118. These defects could not be explained by alterations in protein expression. Likewise, skeletal muscle and adipocytes from obese, insulin-resistant individuals demonstrate impaired insulin-triggered IRS-1 associated PI3K activity compared to matching tissue from lean individuals119,120. 106. Thurmond DC, Pessin JE. Molecular machinery involved in the insulin-regulated fusion of GLUT4-containing vesicles with the plasma membrane. Mol Membr Biol 2001; 18 : 237-45. 112. Min J, Okada S, Kanzaki M, Elmendorf JS, Coker KJ, Ceresa BP, et al. Synip: a novel insulin-regulated syntaxin 4-binding protein mediating GLUT4 translocation in adipocytes. Mol Cell 1999; 3 : 751-60. 113.Yamada E, Okada S, Saito T, Ohshima K, Sato M, Tsuchiya T, et al. Akt2 phosphorylates Synip to regulate docking and fusion of GLUT4-containing vesicles. J Cell Biol 2005; 168 : 921-8. 114. Sano H, Kane S, Sano E, Lienhard GE. Synip phosphorylation does not regulate insulin-stimulated GLUT4 translocation. Biochem Biophys Res Commun 2005; 332 : 880-4. 117. Saltiel AR, Kahn CR. Insulin signalling and the regulation of glucose and lipid metabolism. Nature 2001; 414 : 799-806. 118. Krook A, Bjornholm M, Galuska D, Jiang XJ, Fahlman R, Myers MG, Jr., et al. Characterization of signal transduction and glucose transport in skeletal muscle from type 2 diabetic patients. Diabetes 2000; 49 : 284-92. 119. Bjornholm M, Al-Khalili L, Dicker A, Naslund E, Rossner S, Zierath JR, et al. Insulin signal transduction and glucose transport in human adipocytes: effects of obesity and low calorie diet. Diabetologia 2002; 45 : 1128-35. 120. Brozinick JT, Jr., Roberts BR, Dohm GL. Defective signaling through Akt-2 and -3 but not Akt-1 in insulinresistant human skeletal muscle: potential role in insulin resistance. Diabetes 2003; 52 : 935-41. |
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