DUAL PATHWAYS REGULATING ACTH SECRETION

本项目旨在提供对基本的蜂窝 ACTH释放的调控机制。在两种培养的大鼠前路 在分泌ACTH的AtT20细胞系中， CRF被认为是由环磷酸腺苷介导的。然而，其他 促肾上腺皮质激素分泌物，如血管紧张素、加压素、儿茶酚胺 和佛波酯通过激活ACTH的分泌反应 受体后事件似乎独立于环磷酸腺苷 一代。这些观察结果与更多 而不是一个监管这个系统的机制。血管紧张素转运蛋白受体 垂体前叶似乎是一种V1样受体，它的激活， 在其他组织中，与磷脂代谢的变化有关。 这一过程的代谢产物(即1，2-二酰基甘油)又被 激活一种钙/磷脂依赖的蛋白激酶(C-激酶)。 这项拨款建议的研究将主要涉及这一机制。 AVP的作用及其与CRF的相互作用。这些实验将 证明AVP对磷脂转换以及 C-激酶的激活。事实上，如果CRF主要利用cAMP依赖的 途径，而AVP的作用是通过以下途径介导的 C-激酶，激活这些通路的后果将是 通过对内源性磷酸化底物的探测证明了这一点。这 方法将提供对ACTH版本如何的更好的理解 受多种荷尔蒙的影响。

This project is designed to provide an understanding of the basic cellular mechanisms regulating ACTH release. In both cultured rat anterior pituitary cells and in the ACTH secreting AtT20 cell line, the action of CRF has been proposed to be mediated by cyclic AMP. However, other secretagogues of ACTH such as angiotensin, vasopressin, the catecholamines and phorbol myristate acetate evoke ACTH secretory responses by activating postreceptor events that appear to be independent of cyclic AMP generation. These observations are consistent with the existence of more than one mechanism regulating this system. The AVP receptor in the anterior pituitary appears to be a V1-like receptor, activation of which, in other tissues, is associated with changes in phospholipid metabolism. Metabolities (i.e., 1,2-diacylglycerol) of this process, in turn, have been shown to activate a Ca2+/phospholipid-dependent protein kinase (C-kinase). The studies proposed in this grant will primarily deal with the mechanism of action of AVP and its interaction with CRF. These experiments will demonstrate the effect of AVP on both phospholipid turnover as well as C-kinase activation. If, in fact, CRF primarily utilizes a cAMP-dependent pathway, as previously shown, while the effects of AVP are mediated by C-kinase, the consequences of the activation of these pathways will be demonstrated by probing for endogenous phosphorylated substrates. This approach will provide a better understanding of how ACTH release is regulated by multiple hormonal influences.