[Multiplicity of adenylylcyclase and regulation of G-protein]

Adenylylcyclase is a membrane bound enzyme that catalyzes the conversion of ATP to cyclic AMP. Studies on the regulation of adenylylcyclase have been hampered by the small amount of this enzyme in the cell as well as by the instability of the catalytic activity. Cloning of multiple adenylylcyclase isoforms (types I though VIII) has indicated the presence of a large enzyme family, which is further subdivided into several smaller groups. Members within the same group share similar biochemical properties. The multiplicity of adenylylcyclase is made through at least three distinct mechanisms. First, each isoform is encoded by a distinct gene. Second, multiple isoforms are generated through possible alternative splicing from the same gene. Third, there is a mechanism to generate a half-molecule of adenylylcyclase via alternative polyadenylation. Overexpression of a distinct isoform in insect cells followed by purification has enabled researchers to examine the role of each specific isoform in vitro. The results have suggested that each isoform is regulated through distinct mechanisms. For example, type I adenylylcyclase is inhibited in the presence of beta gamma-subunits, while type II is stimulated. Other isoforms such as types V and VI are not affected. On the other hand, Gi alpha may directly inhibit each adenylylcyclase isoform. Further characterization of adenylylcyclase would be feasible using those clones in the future.