Cyclic AMP-dependent and cyclic AMP-independent antagonism of insulin activation of cardiac glycogen synthase.
The hormonal regulation of glycogen synthase has been studied with isolated perfused hearts that were depleted of 85% of their endogenous glycogen. Glycogen depletion alone promoted a 3-fold activation of glycogen synthase and magnified by 3-fold the response to insulin. Glycogen depletion also facilitated the detection of epinephrine-promoted glycogen synthase inactivation. Hormonal effects on glycogen synthase have been correlated with changes in phosphorylase, phosphorylase kinase, and tissue cAMP levels. Insulin activation of glycogen synthase was observed within 90 s of hormone addition and was maximal by 4 min. A half-maximum effect was obtained at an insulin concentration of 100 microunits/ml. Insulin-dependent activation is reversed by beta-adrenergic agonists, alpha-adrenergic agonists, and glucagon. Each promote the same degree of inactivation and the maximum extent of inactivation produced by each is independent of whether or not the tissue has been stimulated with insulin. beta-Adrenergic agonists and glucagon act via cAMP, alpha-agonists most likely act via intracellular Ca2+ translocation, and insulin action would appear to be independent of either cAMP or Ca2+. The action of epinephrine on cardiac glycogen synthase is mediated by interaction with both alpha- and beta-receptors. As indicated by dose-response curves, receptor occupancy of each occurs to an almost equal extent at suboptimal epinephrine concentrations. Regulation of cardiac glycogen synthase by epinephrine thus is mediated by two second messenger systems which converge to produce the end physiological response.
D000818:Animals; D000242:Cyclic AMP / Q000494:pharmacology*; D004336:Drug Antagonism; D004837:Epinephrine / Q000494:pharmacology; D005934:Glucagon / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology; D006006:Glycogen Synthase / Q000378:metabolism*; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D007328:Insulin / Q000494:pharmacology*; D007545:Isoproterenol / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D009206:Myocardium / Q000201:enzymology*; D010643:Phenoxybenzamine / Q000494:pharmacology; D010764:Phosphorylase Kinase / Q000378:metabolism; D006005:Phosphorylases / Q000378:metabolism; D011433:Propranolol / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D007328:Insulin; D010643:Phenoxybenzamine; D005934:Glucagon; D011433:Propranolol; D000242:Cyclic AMP; D006005:Phosphorylases; D006006:Glycogen Synthase; D010764:Phosphorylase Kinase; D005947:Glucose; D007545:Isoproterenol; D004837:Epinephrine