Molecular and cellular requirements for the regulation of adenylate cyclases by calcium

Calcium-sensitive adenylate cyclases provide a key regulatory device for integrating the activities of the two major signalling systems, Ca²⁺ and cAMP. Recent experiments have brought us closer to understanding the molecular mechanisms whereby Ca²⁺ either stimulates or inhibits susceptible adenylate cyclases in vitro. However, in the intact cell an additional layer of sophistication is evident whereby Ca²⁺-sensitive adenylate cyclases are juxtaposed with Ca²⁺-entry channels, such that the cyclases respond selectively to capacitative Ca²⁺ entry. Part of this dependency is enforced by the placement of Ca²⁺-sensitive adenylate cyclases (AC5, AC6 and AC8) in caveolae, from which at least one Ca²⁺-insensitive adenylate cyclase (AC7) is excluded. However, additional protein–protein interactions are also required to ensure the dependency of these cyclases on capacitative Ca²⁺ entry. Recent findings in this area and their implications for ‘local cAMP signals’ will be discussed.