tailieunhanh - Báo cáo khoa học: Inactivation of phosphorylase is a major component of the mechanism by which insulin stimulates hepatic glycogen synthesis

Multiple signalling pathways are involved in themechanism by which insulin stimulates hepatic glycogen synthesis. In this study we used selective inhibitors of glycogen synthase kinase-3 (GSK-3) and an allosteric inhibitor of phosphory-lase (CP-91149) that causes dephosphorylation of phos-phorylasea, to determine the relative contributions of inactivation of GSK-3 and dephosphorylation of phos-phorylaseaas alternative pathways in the stimulation of glycogen synthesis by insulin in hepatocytes. | Eur. J. Biochem. 270 2773-2781 2003 FEBS 2003 doi j Inactivation of phosphorylase is a major component of the mechanism by which insulin stimulates hepatic glycogen synthesis Susan Alston1 Matthew P. Coghlan2 and Loranne Agius1 1 School of Clinical Medical Sciences University of Newcastle upon Tyne The Medical School Newcastle upon Tyne UK department of Vascular Biology GlaxoSmithKline Harlow Essex UK Multiple signalling pathways are involved in the mechanism by which insulin stimulates hepatic glycogen synthesis. In this study we used selective inhibitors of glycogen synthase kinase-3 GSK-3 and an allosteric inhibitor of phosphorylase CP-91149 that causes dephosphorylation of phosphorylase a to determine the relative contributions of inactivation of GSK-3 and dephosphorylation of phosphorylase a as alternative pathways in the stimulation of glycogen synthesis by insulin in hepatocytes. GSK-3 inhibitors SB-216763 and Li caused a greater activation of glycogen synthase than insulin 90 vs. 40 but a smaller stimulation of glycogen synthesis 30 vs. 150 . The contribution of GSK-3 inactivation to insulin stimulation of glycogen synthesis was estimated to be less than 20 . Dephosphorylation of phosphorylase a with CP-91149 caused activation of glycogen synthase and translocation of the protein from a soluble to a particulate fraction and mimicked the stimulation of glycogen synthesis by insulin. The stimulation of glycogen synthesis by phosphorylase inactivation cannot be explained by either inhibition of glycogen degradation or activation of glycogen synthase alone and suggests an additional role for translocation of synthase. Titrations with the phosphorylase inactivator showed that stimulation of glycogen synthesis by insulin can be largely accounted for by inactivation of phosphorylase over a wide range of activities of phosphorylase a. We conclude that a signalling pathway involving dephosphorylation of phosphorylase a leading to both

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