Abstract
Corticotropin-releasing factor (CRF) receptors represent one of the primary sites for negative feedback of the pituitary by adrenocortical glucocorticoid hormones; however, the molecular mechanisms involved have yet to be elucidated. The present study examines the mechanisms by which glucocorticoids regulate CRF-R1 expression in the pituitary cell line, AtT-20. Treatment of these cells with dexamethasone resulted in a concentration- and time-dependent inhibition of CRF-R1 mRNA that was significant by 1 hr and maximal after 4 hr. Levels of CRF-R1 mRNA then returned to control levels after 24 hr. Similar changes were observed when the cells were treated with corticosterone. Pro-opiomelanocortin mRNA was also decreased after dexamethasone pretreatment; however, the time course was much slower with a significant effect only detected after 6 hr. Further analysis of the mechanisms that mediate glucocorticoid regulation of CRF-R1 mRNA was conducted. These studies demonstrated that glucocorticoid incubation significantly decreases the rate of CRF-R1 gene transcription, as determined by nuclear run-on analysis. In addition, the results demonstrate that glucocorticoid incubation significantly decreases CRF-R1 mRNA stability by approximately 50%. The down-regulation of CRF-R1 mRNA was dependent onde novo protein synthesis, as it was blocked by pretreatment with cycloheximide. This represents a novel mechanism for glucocorticoid negative feedback regulation of CRF-R1 expression.
Footnotes
- Received October 22, 1996.
- Accepted December 20, 1996.
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Send reprint requests to: Ronald S. Duman, Department of Psychiatry, Connecticut Mental Health Center, Yale University School of Medicine, 34 Park St., New Haven, CT 06508. E-mail:ronald.duman{at}quickmail.yale.edu
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This work was supported by United States Public Health Service Grants MH45481, MH53199, DA08227, and 2PO-MH25643; and by the National Center Grant for Post-traumatic Stress Disorder, Department of Veterans Affairs.
- The American Society for Pharmacology and Experimental Therapeutics
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