Role of adenylate cyclase in immunologic release of mediators from rat mast cells: agonist and antagonist effects of purine- and ribose-modified adenosine analogs.

The initial monophasic rise in cyclic AMP beginning 5-15 sec after bridging of rat mast cell IgE-Fc receptors precedes the secretion of granule constituents, thereby implying a causal relationship. Direct evidence for a relationship between IgE-dependent transmembrane activation of adenylate cyclase and granule secretion was provided by the capacity of purine-modified (R site active) and ribose-modified (P site active) adenosine analogs, respectively, to augment and suppress mediator release while simultaneously increasing and decreasing the activity of adenylate cyclase. R site stimulation alone does not cause granule secretion but augments the rate and magnitude of IgE-Fc receptor-induced secretion, reflecting the coupled relationship of such receptors. Inhibition of adenylate cyclase at the P site attenuates the rise in cellular cyclic AMP and suppresses IgE-dependent mediator release in a parallel and superimposable dose-response fashion. Further, the relationship between the attenuation in the rise in cyclic AMP and the diminution in immunologic mediator release is linear with the regression line passing through the origin, indicating a direct relationship between the IgE-dependent activation of adenylate cyclase and preformed mediator release. Although not the only events in coupled mast cell activation--secretion, there is a sequential relationship among perturbation of IgE-Fc receptors, transmembrane activation of adenylate cyclase, elevation of cytoplasmic levels of cyclic AMP, activation of cyclic AMP-dependent protein kinase, and secretion of mast cell granules.