Previous studies involving radioreceptor and functional assays have shown that CRF and glucocorticoids are able to modulate CRF receptors of the brain and anterior pituitary. In this study, we analyzed the effects of CRF, vasopressin (AVP), dexamethasone (DEX), and corticosterone on the regulation of CRF receptor (CRF-R1) messenger RNA (mRNA) levels in cultured rat anterior pituitary cells. CRF decreased CRF-R1 mRNA levels in a time- and concentration-dependent manner. In the presence of 10 nM CRF, CRF-R1 mRNA levels decreased within 1 h (to 65 +/- 3% of the control value; P < 0.01) with a maximal effect after 3 h (to 28 +/- 1% of the control value; P < 0.001). The concentration dependence of the inhibitory effect of CRF at 3 h correlated with that required for ACTH secretion (half-maximal at approximately 0.03 nM). Treatment with a maximal (100 nM) dose of AVP or a submaximal (0.1 nM) dose of CRF for 3 h reduced CRF-R1 mRNA levels to 66 +/- 3% and 53 +/- 6% of the control value, respectively. In the presence of both AVP and CRF, CRF-R1 mRNA levels were 32 +/- 3% of the control value. The incubation of cells for 3 h with 10 microM forskolin to activate adenylate cyclase or with 20 nM 12-0-tetradecanoylphorbol-13-acetate to activate protein kinase C resulted in a decrease in receptor mRNA levels to 40 +/- 9% (P < 0.01) and 28 +/- 8% (P < 0.001) of the control value, respectively, suggesting that the effects of CRF and AVP may be mediated by these pathways. DEX (20 nM) also caused a dose- and time-dependent decrease in mRNA levels. Maximal inhibition was observed after 3 h (to 31 +/- 6% of the control value; P < 0.001), with a partial recovery of mRNA levels at 24 or 48 h. Corticosterone similarly inhibited the accumulation of CRF-R1 mRNA in a dose- and time-dependent manner, but, in contrast to DEX, CRF-R1 mRNA levels returned almost to control levels after 24 h. These results indicate that the ability of CRF, AVP, and glucocorticoids to modulate the responses of corticotropes to CRF may be due in part to the actions of these agents on CRF-R1 mRNA accumulation.
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