MECHANISMS OF HORMONE AND TRANSMITTER SECRETION

激素和递质分泌机制

• 批准号: 3964273
• 负责人: H B POLLARD
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3964273
• 关键词: adrenal glands; ascorbate; calcium metabolism; catecholamines; cell biology; cell membrane; chromaffin cells; cytogenetics; electron microscopy; exocytosis; freeze etching; granule; hormone biosynthesis; hormones; insulin; membrane activity; membrane fusion; membrane permeability; monoclonal antibody; norepinephrine; orphan disease /drug; pancreatic islet function; pancreatic islets; pinocytosis; secretion; tissue /cell culture

Our recent studies have focussed on the processes underlying granule assembly, synthesis and insertion of hormones into granules, movement of granules to sites of secretion and signals leading to membrane contact and fusion between granules and plasma membranes leading to exocytosis in chromaffin cells and Islets of Langerhans, our primary experimental systems. In the chromaffin cell a key element in assembly is the enzyme cytochrome b562, since it is the only "intrinsic membrane protein." We have cloned this protein and are now determining its primary structure. The function of this cytochrome may be to donate electrons to the intragranular enzyme DBH, so that it can convert dopamine to norepinephrine. The origin of the electrons is ascorbic acid. Movement to the site of membrane fusion may be regulated by actin filaments, since dissolution of these filaments potentiates secretion. Secretion signals may include protein kinase C substrates and IP3, as well as calcium. We have purified protein kinase C to homogeneity and are studying its properties. The final event, membrane fusion, may be mediated by synexin, the receptors for which include acidic phospholipids and perhaps specific proteins. Protons may also facilitate synexin action. Secretion signals seem to originate on the plasma membrane, either due to binding to specific receptor or changes in electrical potential. In chromaffin cells nicotinic and muscarinic cholinergic receptors allow calcium to enter the cytosol, from either outside or inside the cell, respectively. In the B cell similar muscarinic receptors mediate secretion, but the site of glucose action remains unresolved. However, both types of secretagogues cause cyclic changes in activity of K+ and Ca++ channels on the plasma membrane, resulting in cyclic changes in the rate of insulin secretion over time. Cyclic nucleotides also regulate coupling and secretory efficiency of B cells. The cytosolic pH may also regulate ionic channel function and secretion, but the latter two processes are not absolutely coupled.

我们最近的研究重点是颗粒的基本过程 激素的组装、合成和插入到颗粒中，激素的运动 颗粒到分泌部位和导致膜接触的信号 颗粒和质膜之间的融合导致胞吐作用 嗜铬细胞和胰岛，我们的主要实验 系统。 在嗜铬细胞中，组装的关键元素是酶 细胞色素 b562，因为它是唯一的“内在膜蛋白”。 我们 已经克隆了这种蛋白质，现在正在确定其一级结构。 这种细胞色素的功能可能是向 颗粒内酶 DBH，从而将多巴胺转化为 去甲肾上腺素。 电子的来源是抗坏血酸。 运动至 膜融合的位点可能受到肌动蛋白丝的调节，因为 这些细丝的溶解增强了分泌。 分泌信号 可能包括蛋白激酶 C 底物和 IP3，以及钙。 我们 已将蛋白激酶 C 纯化至均质并正在研究其 特性。 最终事件，膜融合，可能是由突触蛋白介导的， 其受体包括酸性磷脂，也许还有特定的 蛋白质。 质子还可以促进联联蛋白的作用。 分泌信号 似乎起源于质膜，或者由于与特定的结合 受体或电位的变化。 在嗜铬细胞中烟碱 毒蕈碱胆碱能受体允许钙进入细胞质， 分别来自细胞外部或内部。 在B细胞中 类似的毒蕈碱受体介导分泌，但葡萄糖的位点 行动仍未解决。 然而，两种类型的促分泌剂都会导致 质膜上 K+ 和 Ca++ 通道活性的周期性变化， 导致胰岛素分泌率随时间的周期性变化。 环核苷酸还调节 B 的偶联和分泌效率 细胞。 细胞质 p​​H 值还可以调节离子通道功能 分泌，但后两个过程并不是绝对耦合的。