Regulation by Ca2+-Signaling Pathways of Adenylyl Cyclases

Interplay between the signaling pathways of the intracellular second messengers, cAMP and Ca2+, has vital consequences for numerous essential physiological processes. Although cAMP can impact on Ca2+-homeostasis at many levels, Ca2+ either directly, or indirectly (via calmodulin [CaM], CaM-binding proteins, protein kinase C [PKC] or G beta gamma subunits) may also regulate cAMP synthesis. Here, we have evaluated the evidence for regulation of adenylyl cyclases (ACs) by Ca2+-signaling pathways, with an emphasis on verification of this regulation in a physiological context. The effects of compartmentalization and protein signaling complexes on the regulation of AC activity by Ca2+-signaling pathways are also addressed. Major gaps are apparent in the interactions that have been assumed, revealing a need to comprehensively clarify the effects of Ca2+ signaling on individual ACs, so that the important ramifications of this critical interplay between Ca2+ and cAMP are fully appreciated.