The acinar cell of the exocrine pancreas synthesizes a large number of digestive enzymes that are secreted into the gastrointestinal tract. Both hormonal and dietary factors have been implicated in the regulation of the synthesis of these enzymes. However, the mechanisms whereby this regulation is effected are not known. Further, it is not clear whether regulation of pancreatic enzyme synthesis and secretion are linked via intracellular feedback mechanisms, coupled to respond to the sme stimuli, or independently regulated. We have recently determined that manganese exerts direct effects on pancreatic enzyme secretion and protein synthesis, enhancing synthesis at low concentrations, and inhibiting synthesis at higher concentrations. We have previously shown that cholecystokinin and carbachol, two pancreatic secretagogues that are known to act via Ca++, also exert biphasic effects on pancreatic protein synthesis. Our preliminary findings indicate that the actions of manganese on protein synthesis, like the actions of cholecystokinin and carbachol, are modulated by Ca++. Inasmuch as the exocrine pancreas is rich in manganese, these observations suggest that manganese may act as an intracellular mediator that coordinates the regulation of pancreatic protein synthesis with enzyme secretion. Because 95% of protein synthesis in the pancreas is directed toward the production of exportable digestive enzymes, manganese may thus participate in the regulation of pancreatic enzyme synthesis. To determine the mechanism of action of manganese, we will study its uptake, intracellular localization, effects on Ca++ fluxes, and actions on protein phosphorylation. We will use both short-term preparations of isolated pancreatic acini and long-term cultures of acinar cells. To determine whether there are any interactions between pancreatic secretagogues and manganese, the effects of manganese on these functions will be correlated with the effects of cholecystokinin and vasoactive intestinal polypeptide. The biological significance of these in vitro effects of manganese will be investigated by inducing dietary manganese deficiency in rats, and subsequently in other animal species. We will study the pancreatic ultra-structure, enzyme content and synthesis, and responsiveness to pancreatic secretagogues in pancreatic tissues isolated from manganese-deficient animals. Finally, we will determine whether the pancreas of these animals has the capacity to adapt to dietary alterations.
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