[Desensitization of adenylate cyclase of pigeon erythrocytes under the effects of isoproterenol and cAMP].

Long-term exposure of pigeon erythrocytes to isoproterenol causes substantial changes in the regulatory properties of adenylate cyclase. The enzyme sensitivity to isoproterenol (0.2 mM) and GTP (1.0 mM) decreases by 50% after 20 min incubation, while that to guanylyl imidodiphosphate (0.1 mM), a non-hydrolyzeable analogue of GTP, is lowered by 20-25% after 40 min. The decrease of the enzyme sensitivity to the activators is associated with the appearance of a lag period in the effects of isoproterenol and Gpp(NH)p and with an increase of the lag period in the effect of Gpp(NH)p. The observed desensitization is not concomitant with a reduction of the number of beta-adrenoreceptors but leads to the loss of the Gpp(NH)p ability to induce the dissociation of the receptor-bound hormone. Similar effects were observed after simultaneous addition of 0.1 mM cAMP and 1 mM isobutylmethylxanthine to pigeon erythrocytes, although in this case the degree of desensitization was somewhat lower. Desensitization of adenylate cyclase may occur under conditions preventing the formation of cAMP in the cells as a response to the hormone addition (5 mM CaCl2, 10 micrograms/ml of A23187). Under these conditions, the desensitization is characterized by a lag period in the effects of isoproterenol and Gpp(NH)p and a decrease in the number of isoproterenol-binding sites with a high affinity for the agonist. It is assumed that desensitization is a multistep process that requires both isoproterenol and cAMP.