In pancreas some secretagogues such as cholecystokinin (CCK), acetycholone, bombesin and physalaemin interact with specific classes of receptors to cause mobilization of cellular Ca+2 which results in enzyme secretion. In addition to mobilization of cellular Ca+2, the receptor-ligand interaction with these agents leads to turnover of phosphatidylinositol (PI). In 1975, Michell proposed that PI turnover is the universal biochemical event which is responsible for the Ca+2 gating mechanism. However, in the pancreas, studies have been conflicting regarding the relationship of cellular Ca+2 changes to PI turnover. In order to establish whether PI-turnover is responsible for, or the result of, changes in cellular Ca+2, we will determine time course and dose-response relationships between receptor occupancy by ligand, 45Ca+2 outflux (a measure of Ca+2 mobilization), PI synthesis, PI degradation and amylase secretion in the presence and absence of extracellular Ca+2 for various secretagogues in dispersed guinea pig pancreatic acini. In order to further understand the role of PI turnover in this tissue we will correlate changes in PI metabolism with several unexplained phenomena in this tissue such as CCK-induced desensitization of the acini to all agents that act by mobilizing cellular Ca+2, potentiation of CCK-stimulated enzyme secretion by agents that increase cellular cyclic AMP, submaximal enzyme secretion with supramaximal concentrations of CCK, and manganese-stimulated enzyme secretion which is potentiated by agents that increase cellular cyclic AMP. If successful, these studies will establish the role and position of PI metabolism in the stimulus-secretion coupling process. The results may ultimately have implications regarding the mechanisms of pancreatitis and pancreatic exocrine insufficiency. Furthermore, because PI turnover is a universal biochemical event in tissue where the response is mediated by changes in intracellular Ca+2, the results of these studies will have implications for the stimulus-response mechanism in a variety of tissues.
