Adenosine 3',5'-Monophosphate as the Intracellular Mediator of the Action of Adrenocorticotropic Hormone on the Adrenal Cortex

• Published in: The Journal of biological chemistry 1967-12, Vol.242 (23), p.5535-5541
• Main Authors: Grahame-Smith, D G, Butcher, R W, Ney, R L, Sutherland, E W
• Format: Article
• Language: English
• Subjects: Adrenal Cortex - drug effects; Adrenal Cortex - metabolism; Adrenal Cortex Hormones - biosynthesis; Adrenocorticotropic Hormone - pharmacology; Animals; Cyclic AMP - physiology; Cycloheximide - pharmacology; Hypophysectomy; Male; NADP - pharmacology; Rats
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1016/s0021-9258(18)99390-7

Several pieces of evidence have been established which indicate that adenosine 3',5'-monophosphate is the intracellular mediator of the action of adrenocorticotropic hormone (ACTH) on the adrenal cortex. 1. Increases in adrenal cyclic AMP concentrations induced by ACTH occurred before increases in the rate of adrenal steroidogenesis. 2. Increasing doses of ACTH produced increasing concentrations of adrenal cyclic AMP as steroidogenesis was progressively stimulated, and adrenal concentrations of cyclic AMP remained elevated while the rate of steroidogenesis was maintained. 3. The potency of analogues of ACTH in producing stimulation of adrenal steroidogenesis was reflected in their potency in producing increases in adrenal cyclic AMP concentration. 4. ACTH increased cyclic AMP levels not only in adrenal quarters in vitro and in intact adrenals in vivo but also in adrenal homogenates under conditions which suggested that ACTH was acting to increase adenyl cyclase activity. In addition, cycloheximide, an inhibitor of protein synthesis, although known to inhibit the steroidogenic effects of ACTH or exogenous cyclic AMP did not antagonize the increase in cyclic AMP concentration induced by ACTH. Thus, cycloheximide and, by inference, the newly synthesized protein thought to be involved in steroidogenesis would appear to act at a site past adenyl cyclase. NADPH, which stimulates steroidogenesis but is not antagonized by cycloheximide, had no effect on cyclic AMP levels. This suggests that NADPH acts either at a point distal to both the mechanism producing increased cyclic AMP and past that at which inhibitors of protein synthesis interfere with the reactions leading to stimulation of steroidogenesis, or by a different mechanism. Finally, at a time after hypophysectomy when adrenal weight had fallen and the acute adrenal steroidogenic response to ACTH had disappeared, the sensitivity of the adrenal cyclic AMP response to ACTH was undiminished. The ability of the atropic adrenal to accumulate cyclic AMP in response to ACTH was compatible with the hypothesis that cyclic AMP is involved in the mechanism for the restitution of adrenal growth and steroidogenic capacity.