MECHANISMS OF NEUROENDOCRINE REGULATION

本项目目前的研究重点是调节和 促肾上腺皮质激素释放因子（CRF）受体的作用， CRF与其他ACTH调节剂（包括加压素（VP））的相互作用， 血管紧张素II（AII）、去甲肾上腺素和糖皮质激素。 A. CRF受体调节。 我们之前已经证明， 肾上腺切除术后血浆促肾上腺皮质激素的增加伴随着垂体 34F受体下调和脱敏。 在大鼠中的进一步研究 接受CRF输注证明， 垂体向CRF转化导致CRF受体丢失， CRF刺激的腺苷酸环化酶活性，这可以部分解释 肾上腺切除术后的变化 B。神经系统中的CRF受体。 与之前的调查结果类似， 在大鼠中，在猴中的研究表明CRF受体的存在 在灵长类动物的大脑皮层和边缘系统相关区域 个脑袋 在周围神经系统中，CRF受体的重要性 在离体牛的研究中强调了肾上腺髓质中的 嗜铬细胞，证明CRF的能力，刺激 儿茶酚胺和甲硫氨酸脑啡肽分泌。 C. ACTH调节剂之间的相互作用和作用机制。 在 除了循环AMP依赖性机制，CRF刺激 促肾上腺皮质激素细胞，蛋白激酶C的激活剂如佛波醇酯， 发现合成甘油二酯和磷脂酶C刺激ACTH 分泌物 这种效应是CRF刺激效应的叠加，但 而不是VP，AII和去甲肾上腺素，这表明参与 蛋白激酶C在环腺苷酸非依赖性刺激的作用。 在 关于糖皮质激素反馈，在离体垂体细胞中的实验 表明ACTH分泌的双相抑制模式 在体内观察到的这种情况也发生在体外的促肾上腺皮质激素细胞中。 两 抑制组分具有不同的动力学和对 皮质酮，可能涉及不同的作用机制， 促皮质激素细胞中的糖皮质激素。

Current investigation in this project has focused on the regulation and actions of corticotropin releasing factor (CRF) receptors, and the interactions of CRF with other ACTH regulators including vasopressin (VP), angiotensin II (AII), norepinephrine and glucocorticoids. A. Pituitary CRF receptor regulation. We have previously shown that the increases in plasma ACTH after adrenalectomy are accompanied by pituitary 34F receptor down-regulation and desensitization. Further studies in rats receiving CRF infusion demonstrated that sustained exposure of the pituitary to CRF causes CRF receptor loss and a specific decrease in CRF-stimulated adenylate cyclase activity, which could partially account for the changes following adrenalectomy. B. CRF receptors in the nervous system. Similar to previous findings in the rat, studies in the monkey demonstrated the presence of CRF receptors in the cerebral cortex and limbic system related areas in the primate brain. In the peripheral nervous system, the importance of CRF receptors in the adrenal medulla was emphasized by studies in isolated bovine chromaffin cells which demonstrated the ability of CRF to stimulate catecholamine and met-enkephalin secretion. C. Interactions between ACTH regulators and mechanism of action. In addition to the cyclic AMP-dependent mechanisms by which CRF stimulates the corticotroph, activators of protein kinase C such as phorbol esters, synthetic diacylglycerol and phospholipase C were found to stimulate ACTH secretion. This effect was additive to the stimulatory effect of CRF, but not to those of VP, AII and norepinephrine, suggesting the involvement of protein kinase C in the action of cyclic AMP-independent stimuli. In regard to glucocorticoid feedback, experiments in isolated pituitary cells demonstrated that the biphasic inhibitory pattern of ACTH secretion observed in vivo also occurs in invitro in the corticotroph. The two inhibitory components have different kinetics and sensitivity to corticosterone and probably involve different mechanisms of action of glucocorticoids in the corticotroph.