Corticotropin positively regulates its own receptors and cAMP response in cultured bovine adrenal cells

Abstract

Bovine fasciculata adrenal cells contain specific high-affinity (K(D) ~ 2.3 ± 0.4 x 10-10 M) and low-capacity (1910 ± 300 sites per cell) corticotropin (ACTH) receptors. Pretreatment of cells with ACTH, caused in a time- (maximum effect at 48 hr) and dose- (ED50 ~ 10-11 M, V(max) = 10-10 to 10-9 M) dependent manner an increase in ACTH binding. This was due to a 4-fold increase in the number of binding sites without modification of the binding affinity. The same pretreatment also enhanced the cAMP response to further ACTH stimulation in a dose-dependent manner (ED50 ~ 10-11 M) and to a lesser extent the response to forskolin. However, pretreatment with higher concentrations of ACTH (10-8 M) reduced the binding and the cAMP response when compared to the effect of 10-9 M. These ACTH effects, which were mimicked by 8-bromoadenosine 3',5'-cyclic monophosphate, required de novo protein synthesis. Pretreatment with 10-13 to 10-11 M ACTH also enhanced the steroidogenic responsiveness to further hormonal stimulation. However, at higher concentrations the hormone induced an apparent steroidogenic desensitization that was probably related to a depletion of endogenous cholesterol, since cortisol production in the presence of 22-(R)-hydroxycholesterol was increased. Neither angiotensin-II nor atrial natriuretic factor alone modified ACTH receptors, but angiotensin-II partially blocked the stimulatory effect of ACTH. Thus, ACTH is one of the few polypeptide hormones having a positive trophic effect on its own receptors and target-cell responsiveness.