Chatting Second Messengers: PIP3 and cAMP

3’-5’-cyclic adenosine monophosphate (cAMP) and phosphatidylinositol 3,4,5 trisphosphate (PIP3) are pleiotropic second messengers generated in response to activation of G protein-coupled receptors (GPCRs) by a wide array of hormones and neurotransmitters. Although these small molecules engage distinct and seem-ingly unrelated downstream signal transducers, a growing body of evidence points to a strict cooperation of cAMP and PIP3 cascades in the control of cardiomyocyte functions. Dynamic macromolecular complexes of cAMP and PIP3 molecular switches assemble into spatially and temporally restricted microdomains. Deci-phering how this compartmentalization complexes form and affect the interactions between the two signaling systems is of crucial importance, since both pathways are severely deregulated in major cardiac diseases, such as heart failure. This chapter summarizes recently described mechanisms governing the bidirectional crosstalk between cAMP and PIP3 signaling pathways in the pathophysiological control of cardiovascular function. In particular, we will describe how membrane-located PIP3 affects both initiation and termination of cAMP signaling as well as the negative feedback loop whereby the small and diffusible intracellular messen-ger, cAMP, influences PIP3 production