Adenylylcyclase: Characterization in the Heart and Its Regulation in Heart Failure.

Abstract

It is generally acknowledged that heart failure is characterized by several disorders in cardiac autonomic properties, including sympathetic, parasympathetic and baroreceptor responses. Part of the mechanism of altered cardiovascular control and reduced catecholamine responsiveness in heart failure involves changes in end-organ responses mediated via beta adrenergic receptors. We have now determined the changes that occur in these components during the inception of heart failure induced by cardiac pacing. First, we quantitiated the stoichiometry and function of each of the components of the beta-adrenergic signaling pathway, including the receptor itself, Gs and the adenylylcyclase catalyst. Two key abnormalities occur: (1) the receptor uncouples from Gs, as indicated by loss of high affinity agonist binding sites without a change in receptor density; (2) there is an associated loss adenylylcyclase catalytic activity without any change in the concentration or function of the stimulatory GTP-binding protein Gs. To understand, therefore, what factors underlie the loss in adenylylcyclase catalytic activity; i.e., whether these are the results of a reduced concentration of the catalyst or due to its post-translational modification, we first cloned the cardiac isoforms of adenylylcyclase. Two novel adenylylcyclase cDNAs, types V and VI, were identified that share the motif of tandem six-transmembrane spans separated by a large hydrophilic cytoplasmic loop. Our data suggest that a decrease in the content of the adenylylcyclase catalyst itself contributes to impaired cyclic AMP production in heart failure and may represent a fundamental defect contributing to a progressive decline in LV function. (Hypertens Res 1993; 16: 79-83)