Forskolin requires more than the catalytic unit to activate adenylate cyclase.

Forskolin, a natural diterpene, is a novel, potent activator of a variety of adenylate cyclase systems; its mechanism and site of action are still disputed. We report here that, while forskolin activates liver adenylate cyclase up to 15-fold, it does not activate cyclase of ram sperm which comprises a pure catalytic subunit. However, forskolin activation of sperm adenylate cyclase activity could be observed after reconstitution with the regulatory component-enriched membrane from human erythrocytes. The diterpene weakly (3-5-fold) activated the cytosolic, soluble cyclase found in rat and ram tests, but this effect was lost when the cyclase was purified by gel chromatography. Our data are not compatible with the hypothesis that forskolin acts directly on the catalytic subunit, but rather suggest that it acts via another regulatory component, part of, or different from, the GTP-binding regulatory complex.