Membrane Microdomains and cAMP Compartmentation in Cardiac Myocytes

Abstract

Signaling through the diffusible second messenger, 3′,5′-cyclic adenosine monophosphate (cAMP) is critical to the regulation of cardiac function. Several different G-protein-coupled receptors, including β-adrenergic receptors, muscarinic receptors, and E-type prostaglandin receptors, elicit distinct responses using this ubiquitous second messenger. One critical paradigm that has emerged to explain this behavior is that cAMP signaling is compartmentalized. Spatially confining specific receptors and their downstream effector proteins to form subcellular signaling complexes has been proposed to allow for the high efficiency and fidelity in producing specific functional responses. In cardiac myocytes, lipid rafts created by cholesterol- and sphingolipid-rich membrane microdomains have been demonstrated to act as one means of sorting appropriate receptors and corresponding effectors to relevant subcellular locations. Caveolae, which represent a specific subset of lipid rafts, can dynamically attract or exclude specific signaling proteins through a variety of mechanisms to create highly localized and self-sufficient multi-molecular signaling complexes. Furthermore, disruption of this organization in disease states such as heart failure has been found to alter cAMP responses. In this review, we summarize the current understanding of the role of membrane domains in cAMP signaling in cardiac myocytes. We also highlight the insights gained from previous studies to offer new avenues of research in this expanding field of study.