Protein kinases induce isoproterenol desensitization of beta-adrenoceptor-coupled adenylate cyclase system: significance of receptor occupancy.

Treatment of rat reticulocytes with isoproterenol resulted in dose- and time-dependent desensitization of adenylate cyclase to beta-adrenoceptor agonist stimulation. Cyclic AMP-dependent protein kinase was possibly involved in this desensitization. Treatment of rat reticulocytes with a phorbol ester, tetradecanoyl phorbol acetate (TPA), also induced desensitization to beta-adrenoceptor agonists, indicating the possible involvement of protein kinase C. The addition of a beta-adrenoceptor agonist enhanced the desensitizing effect of dibutyryl cyclic AMP or TPA. T1/2 (time for induction of half maximal desensitization) was decreased from 30 to 2.5 min in accordance with an increase in the concentration of the agonist. The extent of the desensitization was also increased by addition of the agonist. The potency with which the increase was induced was compatible with the potency for binding of the agonist to beta-adrenoceptors (KD values). These results suggest that cyclic AMP- or phorbol ester-induced desensitization is enhanced by receptor occupation by beta-adrenoceptor agonists.