Iredale P A, Terwilliger R, Widnell K L, Nestler E J, Duman R S
Department of Psychiatry, Yale University School of Medicine, Connecticut Mental Health Center, New Haven 06508, USA.
Mol Pharmacol. 1996 Nov;50(5):1103-10.
Corticotropin-releasing factor (CRF) is known to play a major role in coordinating neuroendocrine and behavioral responses to stress. We demonstrate that expression of the CRF1 receptor (CRF-R1) is regulated by stress in the brain and by agonist treatments in cultured cells. Expression of CRF-R1 mRNA was decreased in the frontal cortex but increased in the hippocampus by chronic unpredictable stress. Chronic corticosterone administration did not influence levels of CRF-R1 mRNA in either region, suggesting that regulation of CRF-R1 expression is mediated by CRF itself or by another stress-related factor. Differential regulation of CRF-R1 mRNA by agonist treatment was also observed in two cultured cell lines. In CATH.a cells, a neuron-derived cell line, incubation with CRF decreased levels of CRF-R1 mRNA, whereas in AtT-20 cells, a pituitary-derived cell line, agonist (CRF) treatment increased levels of CRF-R1 mRNA. Further studies demonstrated that the observed changes in both cell lines could be accounted for by regulation of CRF-R1 gene transcription and not by altered mRNA stability. Furthermore, agonist-induced down-regulation of CRF-R1 transcription rate in CATH.a cells was found to be dependent on de novo protein synthesis, suggesting the involvement of an inducible repressor. The results show that different cell types show differential transcriptional regulation of the CRF-R1, which could explain the region-specific regulation of receptor expression in the brain.
促肾上腺皮质激素释放因子（CRF）在协调神经内分泌和对应激的行为反应中起主要作用。我们证明，CRF1受体（CRF-R1）的表达受大脑中的应激以及培养细胞中激动剂处理的调节。慢性不可预测应激使额叶皮质中CRF-R1 mRNA的表达降低，但使海马体中的表达增加。长期给予皮质酮对这两个区域中CRF-R1 mRNA的水平均无影响，这表明CRF-R1表达的调节是由CRF自身或另一种应激相关因子介导的。在两种培养细胞系中也观察到激动剂处理对CRF-R1 mRNA的差异调节。在神经元衍生的细胞系CATH.a细胞中，用CRF孵育会降低CRF-R1 mRNA的水平，而在垂体衍生的细胞系AtT-20细胞中，激动剂（CRF）处理会增加CRF-R1 mRNA的水平。进一步的研究表明，两个细胞系中观察到的变化可以通过CRF-R1基因转录的调节来解释，而不是由mRNA稳定性的改变来解释。此外，发现激动剂诱导的CATH.a细胞中CRF-R1转录速率的下调依赖于从头合成蛋白质，这表明涉及一种可诱导的阻遏物。结果表明，不同细胞类型对CRF-R1表现出不同的转录调节，这可以解释大脑中受体表达的区域特异性调节。
