Background—The cellular content of cAMP generated by activation of adenylylcyclase (AC) through the β-adrenergic receptor (βAR) is a key determinant of a cell’s response to catecholamine stimulation. We tested the hypothesis that increased AC content, independently of βAR 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 βAR number or G-protein content. When stimulated through the βAR, 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 β-adrenergic signaling in vivo, and increased AC, independent of βAR number and G-protein content, provides a means to regulate cardiac responsiveness to βAR 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 β-adrenergic signaling in the heart, suggesting a new target for safely increasing cardiac responsiveness to βAR stimulation.