Classically, adenylyl cyclases respond to receptor-initiated signals, mediated by the Gs and Gi heterotrimeric G proteins. The binding of an agonist to a Gs-coupled receptor (i.e., ? ?-adrenergic receptor) catalyzes the exchange of GDP (bound to G? s) for GTP, dissociation of GTP-G? s from Gbg and G? s-mediated activation of adenylyl cyclase. The most abundant cerebral adenylyl cyclases appears to be adenylyl cyclase IX. AC IX is confined to the gray matter and its expression is mainly neuronal, with its highest expression located at the hippocampus. ACIX is also expressed in heart, pancreas and thyrocytes. AC I and AC IX are regulated reciprocally by intracellular free Ca2+. The inhibition of AC IX by Ca2+ is blocked by the calcineurin inhibitors FK506 and cyclosporin A.