PARATHYROID CHROMOGRANIN A, PANCREASTATIN, PTH RELATION

甲状旁腺激素是钙离子内稳态的关键因素，直到最近才被认为 是甲状旁腺分泌的唯一生物活性多肽。它 现已认识到腺体合成、加工和分泌 另一个主要分子是嗜铬粒素A(CGA，分泌蛋白-I)，它可能 对生物过程产生重大影响。CGA似乎是 普遍分布于内分泌腺，但不分布于外分泌腺。它是 由大约450个氨基酸组成，糖基化、硫酸化和 磷酸化。高纯度甲状旁腺CGA已被证明能抑制 在生理血液浓度下的胰岛素分泌，似乎 胰抑素的前体分子，C端酰胺化的49个氨基酸 酸性多肽，由CGA通过蛋白质分解和酰胺化而得。 胰腺抑素能有效地抑制甲状旁腺的刺激分泌， 内分泌和外分泌胰腺、胃壁细胞，可能还有 肾上腺和其他细胞。除了作为激素和/或激素之外 前体，有人推测CGA改变了细胞内的处理 或包装它的那些分泌颗粒的流量。数据 已有的提高CGA和多肽的真正可能性(S\) 从它衍生出来的，参与了一种迄今未知的内分泌水平 监管和互动。目前的研究集中在以下几个方面 甲状旁腺CGA/胰抑素生物学研究进展。具体目标 包括a)确定胰岛抑素是否以及如何由CGA形成；b) 胰腺抑素抑制作用的生化机制评价(S) 甲状旁腺(和其他细胞)的分泌，包括它对 胞内钙离子，与可能的膜受体相互作用，以及可能的 亲本细胞的自动调节；c)翻译后检查 CGA的修饰及其与1)生物学特性的相关性 分子的活性和2)对“年龄”的作用的评价 骨骼、细胞和组织上的CGA；以及f)筛选其他能够 包括CGA核心氨基酸链的非胰抑素区域，用于 生物活性。从他的调查中获得的信息可能 为正常的内分泌调节和代谢提供新的见解 与内分泌疾病相关的疾病，包括原发和 继发性甲状旁腺功能亢进症、糖尿病和多发性内分泌疾病。

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.