EFFECT OF ANTIRECEPTOR ANTIBODIES IN DILATED CARDIOMYOPATHY ON THE CYCLING OF CARDIAC BETA-RECEPTORS

A substantial proportion of patients with dilated cardiomyopathy have circulating autoantibodies directed against the cardiac-beta-adrenoceptor. These antireceptor antibodies inhibit both ligand binding to membrane-beta-receptors and isoproterenol-sensitive adenylate cyclase. The functional consequences of antibody-receptor interactions were further studied by examining their influence on beta-adrenoceptor cycling. Sera from eight patients with cardiomyopathy induced a loss of beta-receptors from the surface of cardiac myocytes consistent with internalization. This loss was inhibited by concanavalin A, suggesting that receptor sequestration preceded internalization but was unaffected by the cytoskeleton inhibitors colchicine and cytochalasin. In cell-free preparations, serum-induced desensitization of beta-receptors was prevented by heparin but not the inhibitor of protein kinase A; this is consistent with a requirement for receptor phosphorylation by the beta-receptor kinase. In contrast to isoproterenol-mediated endocytosis, beta-receptors internalized under the influence of cardiomyopathic sera do not recycle to the plasma membrane. These results indicate that antireceptor antibodies in human dilated cardiomyopathy induce downregulation by interfering at several steps in the cycling of beta-receptors. These effects would contribute to the reported decline in beta-receptor responsiveness in cardiomyopathic myocardium.