We have found that feeding young female mice a choline-deficient ethionine-supplemented (CDE) diet induces a blockade in the normal process of stimulus secretion coupling in the exocrine pancreas. Secretagogue-receptor binding remains unchanged but the subsequent generation of IP3 from PIP2 by phospholipase C is reduced. As a consequence, the secretagogue-induced rise in cytoplasmic free Ca2+ is attenuated and discharged of digestive enzymes is blocked. The proposed studies will build upon these observations. Four groups of studies are planned. Group 1 will evaluate other stimulus-related events in the exocrine pancreas to determine whether they are blocked by the CDE diet since such an observation would indicate that they occur subsequent to IP3 generation. Group 2 studies will further explore the molecular nature of the lesions induced by the CDE diet. Group 3 studies will evaluate the normal processes of endocytosis and the changes which are induced by the CDE diet. Finally, group 4 studies will explore the effects of the CDE diet on other stimulus-response systems in the mouse as well as the effect of ethionine on stimulus-response systems in cultured cells. These various studies will exploit the CDE diet as a powerful tool with which to explore several important cell biological issues. They will further expand our understanding of stimulus-secretion events in the pancreas. In addition, they will elucidate events which are important components in trans-membrane signaling (i.e. receptor-phospholipase activation) and expand our understanding of the important processes of endocytosis. Finally, these studies may indicate that the CDE diet and/or ethionine can be used to study important aspects of stimulus-response in non-pancreatic tissues and/or cultured cells.
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