MODULATION OF CYCLIC-AMP METABOLISM BY GLUCOCORTICOIDS IN PC18 CELLS

Glucocorticoids modulate signal transduction mechanisms in a number of cell systems. As the adrenal medulla is exposed to relatively high le vels of adrenal cortical glucocorticoids in vivo, particularly during periods of stress, the aim of the present study was to determine wheth er glucocorticoids modulate cyclic AMP (cAMP) metabolism in an in vitr o model of this system, the PC18 cell line. Dexamethasone significantl y potentiated cAMP accumulation in response to the adenosine analogue N-6-R-phenylisopropyl adenosine (PIA), and in response to forskolin. T his effect was both time- and concentration-dependent. Maximal potenti ation was observed after 48 h of exposure to 1 mu M dexamethasone. Cor ticosterone and to a lesser extent aldosterone also significantly pote ntiated PIA-dependent cAMP accumulation. In contrast, estradiol, testo sterone, and triiodothyronine had no potentiative effect. Potentiation could be eliminated by coincubation with the protein synthesis inhibi tor cycloheximide. In the presence of Po 20-1724, a cAMP-phosphodieste rase inhibitor, the degree of potentiation of both PIA- and forskolin- dependent cAMP accumulation was significantly decreased by 50-60%. The se data suggested that altered cAMP-phosphodiesterase activity may be involved in this response. However, cytosolic and membrane-bound low K -m cAMP-phosphodiesterase activity was unchanged in dexamethasone-trea ted cells compared with controls. Similarly, there were no significant differences in basal, PIA-, forskolin-, or GTP gamma S-stimulated ade nylate cyclase activities between groups. These studies indicate that glucocorticoids can potentiate cAMP accumulation in intact PC18 cells. The mechanism underlying this potentiation is likely to be multifacto rial, but may be due in part to decreased cAMP catabolism.