CHEMISTRY AND BIOLOGY OF GUT PANCREASTATIN

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Pancreastatin, a novel 49 amino acid peptide recently isolated from porcine pancreas, has been shown to inhibit glucose stimulated somatostatin and insulin release from the isolated perfused pancreas. These actions of pancreastatin, coupled with its localization in the gastric mucosa (Tatemoto; personal communication), prompted us to examine this peptide's effect on gastric parietal cells. Our preliminary studies indicate that pancreastatin directly inhibits gastrin, carbachol, histamine and dibutyryl cAMP stimulated parietal activity in a fashion that augments the effect of somatostatin. Thus pancreastatin may have physiological importance in regulating gastric acid secretion through unique mechanisms. This background serves as the basis for the proposed studies to examine the physiology and biochemistry of pancreastatin in the gastrointestinal tract. Initial efforts will be directed at developing a sensitive and specific antibody against pancreastatin which will be used to characterize the peptide in gut tissues by immunohistochemistry and radioimmunoassay. Since we have previously observed that biological activity of pancreastatin rests in the carboxyl terminus, we will utilize the heptadecapeptide of the peptide linked to thyroglobulin as immunogen for raising polyclonal antisera in rabbits. Canine gut pancreastatin will be purified and its amino acid sequence determined so that species specific peptide will be available for physiological studies. The effect of pancreastatin on gastric acid secretion will be examined in vivo in dogs with gastric fistulas and the somatostatin and gastrin secretory response to the peptide will be studied in isolated perfused rat stomachs. The cellular basis for pancreastatin action will be determined in preparations of isolated canine gastric parietal, somatostatin, and gastrin cells. The kinetics of pancreastatin binding to parietal cells will be examined using 125I-labeled pancreastatin analogues as ligand. The signal transduction pathways thus activated will be assessed via measurements of cyclic AMP, PI turnover, and membrane associated protein kinase C activity.