Activation and attenuation of adenylate cyclase. The role of GTP-binding proteins as macromolecular messengers in receptor--cyclase coupling.

Since the discovery that cyclic AMP mediates the action of a large number and variety of hormones (Sutherland & Robison, 1966), there has been considerable interest in trying to understand the molecular mechanisms by which hormone occupancy of specific cell surface receptors results in activation of membrane-bound adenylate cyclase, the enzyme responsible for synthesis of cyclic AMP from ATP. Although the earliest concepts of the adenylate cyclase system suggested that hormones might regulate adenylate cyclase activity via binding at allosteric sites on the catalytic moiety, more recently it has been demonstrated that adenylate cyclase systems consist of separable receptor and catalytic subunits (Orly & Schramm, 1976; Limbird & Lefkowitz, 1977; Haga et al., 1977a) and, in addition, a third separable component which confers the multiple regulatory effects of guanine nucleotides on the adenylate cyclase system (for a review focusing on the biochemical properties of the separate components see Ross & Gilman, 1980). The focus of the present review is on these regulatory effects of guanine nucleotides and on the growing body of evidence suggesting that the guanine nucleotide regulatory protein (G-protein) may represent the functional communicator between hormone-occupied receptors and the adenylate cyclase enzyme. The perspective of this review is a historical one; it attempts to summarize the critical observations that established the important role of guanine nucleotides in regulating adenylate cyclase activity and to describe how the further exploration