Interaction of forskolin with dually regulated adenylate cyclase.

Forskolin clearly has effects on all three known components of adenylate cyclase, Ni, Ns, and the catalytic subunit (C). Forskolin can activate the catalytic activity of adenylate cyclase directly in the absence of the Ni or Ns subunit, and, therefore, forskolin is acting at a site that is on the catalytic subunit or a closely associated protein. A lack of forskolin stimulation of cyclic AMP in intact cells does not necessarily imply that it requires or acts via the Ns protein, since, as shown for the cyc- S49 cells, the enzyme may be in an inhibited state because of the presence of Ni. The presence of a site on adenylate cyclase that can regulate not only the absolute activity of the enzyme but also its sensitivity to hormones raises the possibility that there may be substances endogenous to the cell that can functionally interact at this site. It is too early to speculate as to the nature of these substances. However, they could be extracellular, originating from other cells, or they could be intracellular. The final determination will rely on the identification and physical disposition of the forskolin-binding site and also the identification of endogenous compounds with forskolin-like activities.