Genetic manipulation and functional analysis of cAMP signalling in cardiac muscle: implications for a new target of pharmacotherapy.

Adenylate cyclase is a membrane-bound enzyme that catalyses the conversion of ATP into cAMP upon activation of cell-surface G-protein-coupled receptors, such as beta-adrenergic receptors, and initiates a cascade of phosphorylation reactions within the cell. Type 5 adenylate cyclase is a major isoform in the heart as well as in the striatum of the brain. Mice with a disrupted type 5 adenylate cyclase gene exhibited normal cardiac function under basal conditions, but a decreased response to isoprenaline stimulation. When mice were subjected to pressure overload stress with aortic banding, they developed cardiac hypertrophy, but with a significant reduction in the number of apoptotic cardiac myocytes as well as preserved cardiac function. When type 5 adenylate cyclase activity was inhibited pharmacologically, by the use of a novel P-site inhibitor with enhanced selectivity for this isoform, there were no changes in cardiac myocyte contractility, but the development of cardiac myocyte apoptosis induced by isoprenaline stimulation was effectively prevented. These results indicate that type 5 adenylate cyclase may serve as a better target of pharmacotherapy to prevent the development of cardiac myocyte apoptosis and thus failure in response to various cardiac stresses.