The proposed project will enhance our understanding of the events which regulate stimulus-secretion coupling in pancreatic acinar cells. Advantage will be taken of the principal investigator's recent observation that the secretion of digestive enzymes by the mouse pancreas under certain conditions and in response to certain stimuli is inhibited after ingestion of an ethionine-containing diet. For example, in-vivo but not in-vitro basal secretion is reduced after exposure to an ethionine-containing diet. Furthermore, even in-vitro secretion is not totally normal in samples taken from ethionine-fed mice. Under these conditions, CCK-PZ and bethanechol induced secretion is inhibited although calcium ionophore (A-23187) induced secretion is not reduced. In the proposed studies, the effects of an ethionine-containing diet on several of the events believed to couple neurohormonal stimulation with the secretory response will be characterized. Basal, CCK-PZ, cholenergic and ionophore-stimulated secretion will be studied. Hormone binding, Ca2+ fluxes, protein carboxyl methylation, phosphatidyl inositol turnover, and phosphatidic acid generation will be measured. Parallel ethionine-induced effects on the event being studied and the secretory response will support the concept that the two processes are causally linked while divergent effects will indicate that the two are not causally linked. Thus, these studies will clarify the sequence of events which couple stimulus to secretion in the mouse pancreas and identify the mechanism by which this process in inhibited after ingestion of an ethionine-containing diet.
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