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Effect of an Asp905Tyr Mutation of the Glycogen-Associated Regulatory Subunit of Protein Phosphatase-1 on the Regulation of Glycogen Synthesis by Insulin and Cyclic Adenosine 3',5'-Monophosphate Agonists

Diabetes Research Laboratory (L.R., N.D.) Winthrop University Hospital Mineola, New York 11501
School of Medicine (N.B.) State University of New York Stony Brook, New York 11794

The glycogen-associated regulatory subunit of protein phosphatase-1 (PP-1_G) plays a major role in insulin-stimulated glycogen synthesis and thus the regulation of nonoxidative glucose disposal in skeletal muscle. In a general population of Caucasians a polymorphism at codon 905 of PP-1_G from an aspartate to tyrosine has been reported to be associated with insulin resistance and hypersecretion. In this report functional studies were performed on rat skeletal muscle L6 cells stably transfected with an Asp905Tyr mutant PP-1_G to evaluate the impact of this mutation on cellular responsiveness to insulin and cAMP. Although transfection resulted in a 3-fold increase in mutant PP-1_G subunit expression, basal and insulin-stimulated PP-1 catalytic activities were decreased when compared with L6 cells transfected with wild-type PP-1_G. The Asp905Tyr mutation resulted in an increase in cellular sensitivity to cAMP agonist, resulting in an inhibition of insulin’s stimulatory effect on glycogen synthesis. More importantly, low concentrations of (Bu)₂cAMP completely reversed insulin’s stimulatory effects on glycogen synthesis when added to insulin-treated cells expressing mutant PP-1_G. This was due to a rapid activation of glycogen phosphorylase a and a simultaneous inactivation of glycogen synthase via cAMP-mediated reductions in insulin-stimulated PP-1 catalytic activities. We conclude that an Asp905Tyr mutation of PP-1_G is accompanied by a relative increase in sensitivity to cAMP agonists as well as a diminished capacity of the mutant PP-1_G to effectively mediate the inhibitory effects of insulin on glycogen breakdown via PP-1 activation.

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				L. Ragolia, Q. Zuo, and N. Begum Inhibition of Myogenesis by Depletion of the Glycogen-associated Regulatory Subunit of Protein Phosphatase-1 in Rat Skeletal Muscle Cells J. Biol. Chem., August 18, 2000; 275(34): 26102 - 26108. [Abstract] [Full Text] [PDF]