Nanodomain cAMP signaling in cardiac pathophysiology: potential for developing targeted therapeutic interventions

The 3',5'-cyclic adenosine monophosphate (cAMP) mediates the effects of sympathetic stimulation on the rate and strength of cardiac contraction. Beyond this pivotal role, in cardiac myocytes cAMP also orchestrates a diverse array of reactions to various stimuli. To ensure specificity of response, the cAMP signaling pathway is intricately organized into multiple, spatially confined, subcellular domains, each governing a distinct cellular function. In this review, we describe the molecular components of the cAMP signaling pathway with a specific focus on adenylyl cyclases, A-kinase anchoring proteins, and phosphodiesterases. We discuss how they are organized inside the intracellular space and how they achieve exquisite regulation of signaling within nanometer-size domains. We delineate the key experimental findings that lead to the current model of compartmentalized cAMP signaling, and we offer an overview of our present understanding of how cAMP nanodomains are structured and regulated within cardiac myocytes. Furthermore, we discuss how compartmentalized cAMP signaling is affected in cardiac disease and consider the potential therapeutic opportunities arising from understanding such organization. By exploiting the nuances of compartmentalized cAMP signaling, novel and more effective therapeutic strategies for managing cardiac conditions may emerge. Finally, we highlight the unresolved questions and hurdles that must be addressed to translate these insights into interventions that may benefit patients.