Catalyzes the formation of cAMP in response to calcium entry leadings to cAMP signaling activation that affect processes suche as synaptic plasticity and insulin secretion (PubMed:8163524, PubMed:24086669, PubMed:22494970, PubMed:21046358, PubMed:13680124, PubMed:25381556). Plays a role in many brain functions, such as learning, memory, drug addiction, and anxiety modulation through regulation of synaptic plasticity by modulating long-term memory and long-term potentiation (LTP) through CREB transcription factor activity modulation (PubMed:8163524). Plays a central role in insulin secretion by controlling glucose homeostasis through glucagon-like peptide 1 and glucose signaling pathway and maintains insulin secretion through calcium-dependent PKA activation leading to vesicle pool replenishment (PubMed:21046358, PubMed:13680124, PubMed:25381556). Also, allows PTGER3 to induce potentiation of PTGER4-mediated PLA2 secretion by switching from a negative to a positive regulation, during the IL1B induced-dedifferentiation of smooth muscle cells (PubMed:16741924). ATP = 3',5'-cyclic AMP + diphosphate Binds 2 magnesium ions per subunit. Is also active with manganese (in vitro). At rest, the N- and C-terminal domains interact, as part of a larger autoinhibitory complex, with calmodulin pre-associated at the N-terminal domain. Upon a calcium rise, calmodulin becomes calcium-saturated and subsequently binds to the C-terminal domain. Fully calcium-saturated calmodulin then leaves the N-terminal domain, binding solely to the C-terminal domain, and the whole autoinhibitory complex dissociates, resulting in activation of adenylate cyclase. As local calcium concentrations decrease, the calmodulin becomes calcium free and binds once more to the N-terminal domain, whereupon the whole system returns to rest with the re-association of the autoinhibitory complex (PubMed:8163524, PubMed:8557635, PubMed:19305019). In non-excitable cells, activated by capacitative calcium entry (CCE) through store-operated channels, namely through interaction with ORAI1 and STIM1; membrane raft and caveolae localization and membrane integrity are indispensable (PubMed:19158400, PubMed:11744699, PubMed:19171672, PubMed:22494970, PubMed:20410303). CCE-mediated adenylate cyclase activity is decreased by AKAP5 and AKAP7. CCE-mediated adenylate cyclase activity is up-regulated by AKAP9 and the mitochondrially targeted AKAP1 (PubMed:20410303). In excitable cells, activated during membrane depolarization through L-type voltage-gated calcium channels (VGCC), leading to calcium entry; the L-type alpha subunit is sufficient (PubMed:24086669, PubMed:25381556). Activated via stimulation of the GLP1R (PubMed:25381556). Synergistically activated by calcium/calmodulin and GNAS (PubMed:13680124). Stimulated by forskolin (PubMed:16186630, PubMed:13680124). Inhibited by PKA directly bound to AKAP5 at membrane raft (PubMed:22976297, PubMed:21771783). Inhibition by acute activation of OPRM1 and activation by chronic activation of OPRM1 is mediated by pertussis toxin-sensitive G(i) and G(o) G alpha proteins and G beta-gamma dimer. Activity is inhibited by G beta-gamma dimer (PubMed:16186630). Homodimer; via transmembrane domain (PubMed:19158400, PubMed:11856299). Monomer (PubMed:19158400). Heterodimer (PubMed:11856299). Oligemer; via transmembrane domain (PubMed:11856299). Interacts with PRKAR2A and AKAP5; inhibits adenylate cyclase activity through PKA phosphorylation (PubMed:22976297). Interacts with PPP2CA and PPP2R1A; does not mediate the inhibitory effects of PKA on adenylate cyclase activity; interaction is dependent of catalytically active PPP2CA; antagonizes interaction with calmodulin (PubMed:22976297, PubMed:16258073). Interacts with AKAP5 (palmitoylated form); promotes the phosphorylation of ADCY8 after store-operated calcium entry (SOCE) stimulation at membrane raft (PubMed:21771783, PubMed:20410303). Interacts with ORAI1; interaction is calcium store depletion independent; interaction occurs in membrane raft; interaction increases markedly after store depletion; positively regulates SOCE-induced adenylate cyclase activity; contributes to the targeting of ADCY8 to discrete regions of the plasma membrane that are shielded from other calcium events (PubMed:22494970). Interacts with STIM1 (PubMed:22494970). Interacts with actin; interaction is calcium independent; interaction is affected by calcium-calmodulin; interaction controls the distribution and regulation of ADCY8 (PubMed:22399809). Interacts with calmodulin; at rest, interacts via N-terminal domain; upon a calcium rise, calmodulin becomes calcium-saturated and subsequently binds to the C-terminal domain forming an autoinhibitory complex; fully calcium-saturated calmodulin leaves the N-terminal domain, binding solely to the C-terminal domain leading to dissociation of autoinhibitory complex and resulting in activation of adenylate cyclase; antagonizes interaction with PPP2CA; interaction is calcium dependent (PubMed:19305019, PubMed:16258073, PubMed:22399809). Interacts with PPP2R5D (PubMed:22976297). Localized to dendritic arbors (By similarity). Monomeric N-glycosylated specieslocalized in membrane raft. In contrast, monomeric unglycosylated forms are enriched in clathrin-coated pits and vesicles. Dimers are also localized outside of membrane rafts. Membrane raft localization and integrity is indispensable for CCE-stimulated adenylate cyclase activity (PubMed:19158400). Brain (PubMed:13680124, PubMed:8557635). Expressed in insulin-producing cells (PubMed:13680124). Reduces by glucose (PubMed:21046358). Up-regulated during vascular smooth muscle cell de-differentiation by IL1B (PubMed:16741924). The protein contains two modules with six transmembrane helices each; both are required for catalytic activity. Isolated N-terminal or C-terminal guanylate cyclase domains have no catalytic activity, but when they are brought together, enzyme activity is restored. The active site is at the interface of the two domains. Both contribute substrate-binding residues, but the catalytic metal ions are bound exclusively via the N-terminal guanylate cyclase domain. The two transmembrane clusters are necessary and suficient for the plasma membrane targeting and oligomers assembly (PubMed:11856299). The N-terminal and C-terminal domains interact at rest as part of a larger autoinhibitory complex, with calmodulin pre-associated at the N-terminal domain; the binding is specifically inhibited by fully calcium-saturated calmodulin, resulting in activation of AC8 (PubMed:19305019). Phosphorylated by PKA; mediates inhibition of adenylate cyclase activity at membrane raft; does not influence either CALM1 or PPP2CA interaction with ADCY8. N-glycosylated; N-glycosylation is responsible for raft-targeting; is not necessary for CCE-stimulated adenylate cyclase activity. N-glycosylated; N-glycosylation is responsible for raft-targeting; is not necessary for CCE-stimulated adenylate cyclase activity. EC50 is approximately 4 times more sensitive to stimulation by calcium/calmodulin than isoform 1 and 2. Belongs to the adenylyl cyclase class-4/guanylyl cyclase family.