DUAL PATHWAYS REGULATING ACTH SECRETION

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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.