Visual Abstract - Cardiac-Directed Expression of Adenylyl Cyclase Catalytic Domain Reverses Cardiac Dysfunction Caused by Sustained Beta-Adrenergic Receptor Stimulation: 10.1016/j.jacbts.2016.08.004

• Cardiac-targeted expression of C1C2 reduces cAMP production yet mice maintain normal cardiac function through increased Ca2+ handling.

• Sustained isoproterenol infusion reduces heart function in normal mice, but improves heart function in mice with increased cardiac C1C2 expression.

• Reduced cardiac cAMP generation and resistance to catecholamine cardiomyopathy are attractive features of this potential heart failure therapeutic.

• Removing the large transmembrane domains of AC6 and fusing the two intracellular domains provides a small molecule, C1C2, that replicates many of the beneficial effects of AC6, but is sufficiently small to be expressed in an AAV vector for gene transfer.