cAMP is a ubiquitous second messenger mediating cellular responses to various exogenous and endogenous signaling molecules. cAMP regulates physiological processes by activating protein kinases, gating specific ion channels, modulating cellular cyclic nucleotide concentrations through phosphodiesterases, and activating Epac (exchange protein directly activated by cAMP). The conversion of ATP to cAMP is catalyzed by adenylyl cyclases (ACs). The major family of ACs in mammals is the transmembrane ACs which have nine isoforms and could be activated by G protein Gs and/or Ca2+/calmodulin. There is also one soluble AC which could be modulated by bicarbonate and/or Ca2+.