Regulation of Adenylate Cyclase by Hormones and Guanine Nucleotides in Normal, Desensitized, and Resensitized Rabbit Heart

Abstract

According to data obtained for different tissues, desensitization of the adenylate cyclase system in the myocardium is a reversible process which can be turned off in vivo with drugs known to decrease the catecholamine level. Contrary to the data obtained in other tissues (1,10,20), we found that resensitization of the myocardial adenylate cyclase system can occur in a simple system containing only plasma membranes and a beta-receptor antagonist. Ethanol, which changes the fluidity of the membrane and may alter the strength of the hydrophobic interactions among the protein components of the cyclase system, as well as dithiothreitol, which affects agonist binding to the beta-adrenergic receptors, can also produce resensitization of adenylate cyclase in vitro. The desensitized state of the beta-adrenergic receptors and adenylate cyclase in a number of tissues is sensitive to guanine nucleotides but not to the antagonist of the hormone (1,10,11,20). In our experiments on the myocardial membrane, we found that preincubation with guanine nucleotides does not change the number of binding sites for the hormone and its antagonist but increases the effect of the antagonist during resensitization of beta receptors. One of the most unusual effects is the hormone-nonspecific desensitization of myocardial adenylate cyclase: in vivo and in vitro desensitization to catecholamines makes the enzyme sensitive to the inhibitory effect of glucagon. The inhibition of basal and guanine nucleotide-activated adenylate cyclase by alprenolol demonstrated that in the myocardium the desensitized beta receptors were able to activate the enzyme. According to data that demonstrate the inhibition of catecholamine-stimulated adenylate cyclase by glucagon, we can interpret the inhibition of desensitized adenylate cyclase by glucagon in terms of competition for the enzyme between the glucagon receptors and desensitized beta-adrenergic receptors. Resensitization of the adenylate cyclase system reduces the activating effect of guanine nucleotides and the inhibitory effect of the antagonist, increases the stimulatory effect of catecholamines, and reverses the inhibitory effect of glucagon on activation. In myocardium as in other tissues (1,10,11,20), resensitization does not change the affinity of the adenylate cyclase system for guanine nucleotides, catecholamines, and their antagonists but increases the binding capacity of the beta-adrenergic receptors in the membranes (9).