Posttranslational modulation of glucocorticoid feedback inhibition at the pituitary level.
Diagnostic tests of hypothalamic-pituitary-adrenocortical function in psychiatric illness largely report the interaction of hypothalamic secretagogues with glucocorticoids at the pituitary level. This study investigated whether the efficiency of glucocorticoid inhibition is subject to modulation by intracellular processes that enhance cAMP accumulation and/or facilitate membrane depolarization. The secretion of ACTH induced by corticotropin-releasing factor (CRF; 0.1 nM) in primary cultures of rat anterior pituitary cells was markedly inhibited upon a 2-h exposure to 100 nM corticosterone. Arginine vasopressin (2 nM) enhanced the cAMP as well as the ACTH responses to CRF and reduced the efficiency of glucocorticoid inhibition of ACTH release. The action of arginine vasopressin was mimicked by rolipram, an inhibitor of cyclic nucleotide phosphodiesterase type 4. Application of the broad specificity K(+) channel blockers clofilium and astemizole produced minor or no significant enhancement of CRF-induced ACTH release, respectively, but opposed the inhibitory effect of corticosterone. Specific blockers of HERG, KCNQ, and Isk channels had no effect on ACTH release under any condition examined. In summary, these data reveal multiple sites of posttranslational modulation of adrenal corticosteroid action at the level of the pituitary gland, which appear important for the outcome of diagnostic tests of hypothalamic-pituitary- adrenocortical function.
Lim
Min Chin
MC
Medical Research Council Brain Metabolism Unit, Department of Neuroscience, University of Edinburgh, Scotland, United Kingdom EH8 9JZ.
Shipston
Michael J
MJ
Antoni
Ferenc A
FA
D000324:Adrenocorticotropic Hormone / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001127:Arginine Vasopressin / Q000494:pharmacology; D002478:Cells, Cultured; D003345:Corticosterone / Q000037:antagonists & inhibitors / Q000494:pharmacology; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis; D005246:Feedback; D005938:Glucocorticoids / Q000037:antagonists & inhibitors*; D008297:Male; D010903:Pituitary Gland, Anterior / Q000187:drug effects* / Q000378:metabolism*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011499:Protein Processing, Post-Translational; D051381:Rats; D017208:Rats, Wistar
D005938:Glucocorticoids; D026902:Potassium Channel Blockers; D001127:Arginine Vasopressin; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D000242:Cyclic AMP; D003345:Corticosterone