PARATHYROID CHROMOGRANIN A, PANCREASTATIN, PTH RELATION

甲状旁腺素是钙稳态的关键因子，直到最近才被认为是 是甲状旁腺分泌的唯一生物活性肽。它 现在认识到腺体合成，处理和分泌 另一种主要分子，嗜铬粒蛋白A（CgA，分泌蛋白-I）， 对生物过程产生重大影响。 CGA似乎是 普遍分布于内分泌腺而非外分泌腺。 是 由约450个氨基酸组成，并且是糖基化的、硫酸化的和 磷酸化。 高纯度的甲状旁腺CgA已经显示出抑制 在生理血液浓度下的胰岛素分泌， 胰抑素前体分子，C-末端酰胺化的49个氨基酸 酸性肽，其通过蛋白水解和酰胺化从CgA衍生。 胰蛋白酶抑制素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 前体，有推测说，CgA修改细胞内加工 或运输包装它的那些分泌颗粒。 数据 已经可用的提高了CgA和肽（s\） 衍生自它参与了迄今未知的内分泌水平， 调节和互动。 目前的研究集中在几个方面。 甲状旁腺中CgA/胰蛋白酶抑制剂生物学方面。 具体目标 包括a）确定胰抑素是否以及如何由CgA形成; B） 胰抑素抑制的生化机制的评价 甲状旁腺（和其他细胞）的分泌，包括其对 胞浆Ca 2+，与假定的膜受体的相互作用，以及可能的 亲本细胞的自身调节; c）翻译后 CgA的修饰以及这些变化与1）生物学特性的相关性 活性的分子和2）的“年龄”的评价行动 CgA在骨上以及在细胞和组织上的作用;和f）筛选 包括Cga核心氨基酸链的非胰蛋白酶抑制素区， 生物活性 他在调查中获得的信息可以 为正常内分泌调节和代谢提供了新的见解 与内分泌疾病相关的疾病，包括原发性和 继发性甲状旁腺功能亢进、糖尿病和多种内分泌疾病。

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.