Ca++ inhibition of isoproterenol responses in mammalian skeletal muscle.
In noncontracting mouse hemidiaphragms incubated in modified Krebs-Ringer--bicarbonate buffer with 10 mM Ca++, isoproterenol-stimulated phosphorylase a formation, conversion of phosphorylase kinase to the activated form, elevation of cyclic AMP-dependent protein kinase activity ratios and increase in cyclic AMP concentrations were reduced 35 to 50% over the responses in buffer with 2.5 mM Ca++. In buffer with 10 mM Ca++, the initial rate of isoproterenol-stimulated cyclic AMP accumulation was 59% of that in buffer with 2.5 mM Ca++. The inhibitory action of Ca++ on cyclic AMP accumulation was antagonized by verapamil, but not by inhibitors of cyclic nucleotide phosphodiesterase activity. In buffer with 2.5 mM Ca++, isoproterenol-stimulated cyclic AMP accumulation was inhibited by A23187 and caffeine, agents that can increase intracellular Ca++ concentrations. In addition to Ca++, high concentrations of Co++, Ni++, Mn++ and, to a lesser extent, Sr++ inhibited the isoproterenol response. The results of these studies indicate that high buffer Ca++ concentrations inhibit the response of the glycogenolytic pathway to isoproterenol by an action on cyclic AMP formation. We propose that the site of the inhibitory action of Ca++ is the divalent metal activator site associated with hormone-stimulated adenylate cyclase activity.
D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology*; D002413:Cations, Divalent / Q000494:pharmacology; D006152:Cyclic GMP / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D009132:Muscles / Q000187:drug effects* / Q000378:metabolism; D010764:Phosphorylase Kinase / Q000378:metabolism; D010762:Phosphorylase a / Q000096:biosynthesis
D002413:Cations, Divalent; D010762:Phosphorylase a; D010764:Phosphorylase Kinase; D006152:Cyclic GMP; D007545:Isoproterenol; D002118:Calcium