Adenylyl cyclases (ACs) convert ATP into the classical second messenger cyclic adenosine monophosphate (cAMP). Cardiac ACs, specifically AC5, AC6, and AC9, regulate cAMP signaling controlling functional outcomes such as heart rate, contractility and relaxation, gene regulation, stress responses, and glucose and lipid metabolism. With so many distinct functional outcomes for a single second messenger, the cell creates local domains of cAMP signaling to correctly relay signals. Targeting of ACs to A-kinase anchoring proteins (AKAPs) not only localizes ACs, but also places them within signaling nanodomains, where cAMP levels and effects can be highly regulated. Here we will discuss the recent work on the structure, regulation and physiological functions of AC9 in the heart, where it accounts for <3% of total AC activity. Despite the small contribution of AC9 to total cardiac cAMP production, AC9 binds and regulates local PKA phosphorylation of Yotiao-IKs and Hsp20, demonstrating a role for nanometric targeting of AC9.

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