ADRENOCORTICOTROPIN INDUCTION OF STRESS-ACTIVATED PROTEIN-KINASE IN THE ADRENAL-CORTEX IN-VIVO

A broad array of stressors induce ACTH release from the anterior pitui tary, with consequent stimulation of the adrenal cortex and release of glucocorticoids critical for survival of the animal, ACTH stimulates adrenocortical gene expression in vivo and inhibits adrenocortical cel l proliferation, Binding of ACTH to its G-protein-coupled receptor sti mulates the production of cAMP and activation of the protein kinase A pathway, The stress-activated protein kinases (SAPKs) (or c-Jun N-term inal kinases) and the extracellular signal-regulated kinases (ERKs) ar e members of the mitogen-activated protein kinase family of serine/thr eonine kinases, which have recently been implicated in G-protein-coupl ed receptor intracellular signaling, The SAPKs are preferentially indu ced by osmotic stress and UV light, whereas the ERKs are preferentiall y induced by growth factors and proliferative signals in cultured cell s, In these studies, ACTH stimulated SAPK activity 3-4-fold both in th e adrenal cortex in vivo and in the Y1 adrenocortical cell line, 12-O- Tetradecanoylphorbol-13-acetate but not cAMP induced SAPK activity in Y1 cells, The isoquinolinesulfonamide inhibitors H-8 and H-89 blocked ACTH induction of SAPK activity at protein kinase C inhibitory doses b ut not at protein kinase A inhibitory doses, The calcium chelating age nt EGTA inhibited ACTH-induced SAPK activity and the calcium ionophore A23187 induced SAPK activity S-fold, In contrast with the induction o f SAPK by ACTH, ERK activity was inhibited in the adrenal cortex in vi vo and in Y1 adrenal cells, Together these findings suggest that ACTH induces SAPK activity through a PKC and Ca+2-dependent pathway. The in duction of SAPK and inhibition of ERK by ACTH in vivo may preferential ly regulate target genes involved in the adrenocortical stress respons es in the whole animal.