Mechanisms of cAMP compartmentation in cardiac myocytes: experimental and computational approaches to understanding

The small diffusible second messenger 3′,5′‐cyclic adenosine monophosphate (cAMP) is found in virtually every cell in our bodies, where it mediates responses to a variety of different G protein coupled receptors (GPCRs). In the heart, cAMP plays a critical role in regulating many different aspects of cardiac myocyte function, including gene transcription, cell metabolism, and excitation‐contraction coupling. Yet, not all GPCRs that stimulate cAMP production elicit the same responses. Subcellular compartmentation of cAMP is essential to explain how different receptors can utilize the same diffusible second messenger to elicit unique functional responses. However, the mechanisms contributing to this behaviour and its significance in producing physiological and pathological responses are incompletely understood. Mathematical modelling has played an essential role in gaining insight into these questions. This review discusses what we currently know about cAMP compartmentation in cardiac myocytes and questions that are yet to be answered. figure legend Compartmentation of receptor dependent cAMP signalling in adult cardiac ventricular myocytes depends on many factors, including localized production by different G‐protein coupled receptors, localized degradation by phosphodiesterases, buffering by protein kinase A, and restricted diffusion involving tight spaces such as the dyadic cleft.