Selective blockage by islet-activating protein, pertussis toxin, of negative signal transduction from receptors to adenylate cyclase.

Abstract

The adenylate cyclase-cyclic AMP system is one of the signal transduction processes that has been the subject of extensive studies in recent years. Stimulation of some membrane receptors (“activatory” receptors) by particular agonists produces, via activation of adenylate cyclase, cyclic AMP, which acts as an intracellular second messenger of the receptors by activating one of the several kinds of cytosolic protein kinases. The receptor-linked adenylate cyclase system is now known to consist of three components; the guanine nucleotide-binding protein usually referred to as N, G, or G/F, has been identified as the functional communicator between receptors (R) and the catalytic unit of the cyclase (C). A growing body of evidence has accumulated in support of the concept that N plays the pivotal role in receptor-mediated activation of adenylate cyclase, as reviewed by Ross and Gilman (1), Limbird (2) and Spiegel and Downs (3). When no extracellular signal is available to the cell, the species of the guanine nucleotide bound to N is GDP, which allows functional dissociation of the three components, R, N, and C. If information is transmitted by an agonist (A) which occupies R, the ternary complex, A-R-N is formed as the “turn-on” reaction which leads to replacement of GDP by intracellular GTP at the specific binding sites on N. The adenylate cyclase enzyme is then activated as a result of association of the GTP-bound N with C. Synthesis of cyclic AMP continues until GTP is hydrolyzed by the GTPase “turn-off” reaction, leaving GDP on N.