REGULATION OF ADENOSINE 3'-5'-MONOPHOSPHATE CONTENT OF HUMAN ASTROCYTOMA-CELLS - DESENSITIZATION TO CATECHOLAMINES AND PROSTAGLANDINS

Abstract

Human astrocytoma cells (1321N1) exhibit adenylate cyclase activities coupled to independent receptors for catecholamines and prostaglandins of the E-series. Exposure of the cells to norepinephrine or prostaglandin E1 (PGE1) results in an initial rapid accumulation of cyclic AMP but also results in a progressive loss of responsiveness of the cells to agonists. Initially, the desensitization is agonist specific. With continued exposure to high concentrations of norepinephrine, partial loss of responsiveness to PGE1 occurs, and vice versa. The mechanism underlying this phenomenon does not appear to involve inactivation of the effectors, formation of an inhibitory substance in the culture medium or an increase in the rate of excretion of cyclic AMP from the cell. Blockade of protein synthesis (85%) by 5 .mu.g/ml cycloheximide did not change the rate or extent of desensitization. When desensitized cells were incubated in the presence of the effectors, responsiveness was essentially completely recovered with a t1/2 of 5-7 h. Cycloheximide did not delay the onset of recovery nor was the initial rate of recovery reduced. Norepinephrine-induced desensitization to norepinephrine or PGE1 was blocked by sotalol, a .beta.-receptor blocking agent. Incubation of the cells with dibutyryl cyclic AMP caused desensitization to norepinephrine and PGE1. Catecholamine-induced desensitization may occur as a result of interaction of the agonist with the same receptor that is linked to activation of adenylate cyclase. Cyclic AMP appears to mediate at least the nonspecific aspect of agonist-induced desensitization.