Adenylylcyclase increases responsiveness to catecholamine stimulation in transgenic mice

Background-The cellular content of cAMP generated by activation of adenylylcyclase (AC) through the beta-adrenergic receptor (beta AR) is a key determinant of a cell's response to catecholamine stimulation. We tested the hypothesis that increased AC content, independently of beta AR number, increases responsiveness to catecholamine stimulation in vivo. Methods and Results-Transgenic mice with cardiac-directed expression of AC(VI) showed increased transgene AC expression but no change in myocardial beta AR number or G-protein content. When stimulated through the beta AR, cardiac function was increased, and cardiac myocytes showed increased cAMP production. In contrast, basal cAMP and cardiac function were normal, and long-term transgene expression was not associated with abnormal histological findings or deleterious changes in cardiac function. Conclusions-The amount of AC sets a limit on cardiac beta-adrenergic signaling in vivo, and increased AC, independent of beta AR number and G-protein content, provides a means to regulate cardiac responsiveness to beta AR stimulation. Overexpressing an effector (AC) does not alter transmembrane signaling except when receptors are activated, in contrast to receptor/G-protein overexpression, which yields continuous activation and has detrimental consequences. Our findings establish the importance of AC content in modulating beta-adrenergic signaling in the heart, suggesting a new target for safely increasing cardiac responsiveness to beta AR stimulation.