PARATHYROID CHROMOGRANIN A, PANCREASTATIN, PTH RELATION

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Parathormone, a key factor in Ca2+ homeostasis, was thought until recently to be the only biologically active peptide secreted by the parathyroid. It is now recognized that the gland synthesizes, processes and secretes another major molecule, chromogranin A (CgA, Secretory Protein-I) that may exert significant effects on biological processes. CgA appears to be universally distributed in endocrine, but not exocrine, glands. It is composed of about 450 amino acids and is glycosylated, sulfated and phosphorylated. Highly purified parathyroid CgA has been shown to inhibit insulin secretion at physiological blood concentrations and appears to be the precursor molecule for pancreastatin, a C-terminally amidated 49 amino acid peptide, that is derived from CgA by proteolysis and amidation. Pancreastatin potently inhibits stimulated secretion by the parathyroid, endocrine and exocrine pancreas, gastric parietal cells, and possibly the adrenal and other cells. In addition to acting as a hormone and/or hormone precursor, there is speculation that CgA modifies intracellular processing or traffic of those secretory granules in which it is packaged. The data already available raise the real possibility that CgA and peptide(s\) derived form it are involved in a hitherto unsuspected level of endocrine regulation and interaction. The present research focuses on several aspects of CgA/pancreastatin biology in the parathyroid. Specific Aims include a) determination if and how pancreastatin is formed from CgA; b) evaluation of the biochemical mechanism(s) by which pancreastatin inhibits secretion by the parathyroid (and other cells), including its effect on cytosolic Ca2+, interaction with putative membrane receptors, and possible autoregulation of the parent cell; c) examination of posttranslational modifications of CgA and correlation of these changes to 1) the biological activity of the molecule and 2) to the "age" of the evaluation of action of CgA on bone and on cells and tissues; and f) screening other peptides that comprise non-pancreastatin regions of the Cga core amino acid chain for biological activity. The information obtained int his investigation could provide new insights into normal endocrine regulation and into metabolic disorders associated with endocrine diseases including primary and secondary hyperparathyroidism, diabetes and multiple endocrinopathies.