EFFECTERS OF CYCLIC ADENOSINE 5'-MONOPHOSPHATE UP-REGULATING-OXYTOCINRECEPTORS IN RABBIT AMNION CELLS - ISOPROTERENOL, PARATHYROID HORMONE-RELATED PROTEIN, AND POTENTIATION BY CORTISOL

Forskolin (FSK; an activator of adenylyl cyclase) and cortisol synergi stically increase the concentration of oxytocin receptors (OTRs) in ra bbit amnion cells. The aims of this study were to characterize potenti al physiological regulators of OTR concentrations acting through adeny lyl cyclase and to clarify the mechanisms of potentiation by cAMP and cortisol. Both isoproterenol (ISO) and parathyroid hormone-related pro tein (PTHrP) elevated amnion cell cAMP levels and OTR concentrations. The effects of ISO and PTHrP on OTR were potentiated by cortisol. Cort isol had no effect on the ability of ISO or PTHrP to stimulate adenyly l cyclase activity, and cAMP did not affect the number or affinity of glucocorticoid receptors in whole cells or in cytosol. Adenylyl cyclas e activation, however, caused conversion of mifepristone (RU486) from a glucocorticoid antagonist to agonist. Thus, mifepristone elevated OT R receptor concentrations in the presence of FSK. In contrast, a struc turally related glucocorticoid antagonist, onapristone (ZK98 299), was unaffected by cAMP. Because glucocorticoid receptors bound to mifepri stone are capable of interacting with DNA, whereas onapristone-occupie d receptors are not, we conclude that cAMP affects glucocorticoid rece ptor-DNA interactions, accounting for the synergistic effects of cAMP and cortisol on OTRs.