MECHANISMS OF HORMONE AND TRANSMITTER SECRETION

激素和递质分泌机制

• 批准号: 3776186
• 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/3776186
• 关键词: Langerhans' cell; amyloid proteins; annexins; calcium channel; chloride channels; chromaffin cells; cystic fibrosis; exocytosis; genetically modified animals; glucose metabolism; granule; hexokinase; hormone regulation /control mechanism; laboratory mouse; lipid bilayer membrane; membrane fusion; membrane potentials; mucins; neurotransmitter metabolism; pancreatic islets; potassium channel; secretion; tissue /cell culture; xanthine analog

Our work continues to focus on the processes leading to fusion between granule and plasma membranes during exocytotic secretion from cells, including chromaffin cells, beta cells from Islets of Langerhans, nerve terminals, and mucin secreting cells from tissues affected by cystic fibrosis. The contact and fusion processes during secretion may be mediated by the calcium binding protein synexin (annexin VII). We have learned that Annexin VII is immunolocalized to formed elements in the cytoplasm of chromaffin cells, including the chromaffin granule membranes. Annexins, I, II and V can also be detected in these and other cells, but their distribution if different from that of synexin. Potassium channels have also been shown to occur on chromaffin granule membranes, although they are not sensitive to calcium. The role of these channels may be to rearrange [K] in recycling granules following exocytosis. In pituitary gonadotophs the potassium channels controlling the membrane potential are apamine sensitive, and regulate oscillations in membrane potential and internal calcium concentration. The mechanism of oscillation of calcium within these cells depends upon IP3 metabolism. In islets of Langerhans, glucose has a complex effect on intracellular calcium and secretion. The steady state effect of glucose is to induce rhythmic oscillations in intracellular calcium and electrical potential, but the earliest action of glucose is to lower the calcium ion concentration. A transgenic mouse with yeast hexokinase in the insulin secretion, which is lacking in neonatal islets, but is induced by exposure of the islets of prolactin. We have also developed a potential drug for cystic fibrosis based on our observation that the A1-receptor antagonist, 8-cyclopentyl-1,3-dipropyl xanthine activates chloride efflux from human epithelial and mouse fibroblast cell lines bearing the CFTR (delta F508) mutation but not the wild type CFTR. We have also learned that the Alzheimer's disease amyloid forms ion channels in bilayer membranes, and that this activity may be the basis of amyloid neurotoxicity in this disease.

我们的工作继续集中在导致融合的过程中， 颗粒和质膜， 包括嗜铬细胞，胰岛β细胞，神经 终末和粘蛋白分泌细胞从受囊性病变影响的组织 纤维化 分泌过程中的接触和融合过程可能是 由钙结合蛋白synexin（膜联蛋白VII）介导。 我们有 了解到膜联蛋白VII是免疫定位于形成的元素， 嗜铬细胞的细胞质，包括嗜铬颗粒 膜。 膜联蛋白I、II和V也可以在这些和 其他细胞，但它们的分布，如果不同的synexin。 钾通道也被证明存在于嗜铬颗粒上 膜，尽管它们对钙不敏感。 的作用 这些通道可以在以下循环颗粒中重新排列[K 胞吐作用 在垂体促性腺激素细胞中， 膜电位对阿帕胺敏感，并调节振荡 细胞膜电位和细胞内钙离子浓度。 机制 这些细胞内钙离子的振荡依赖于IP 3 新陈代谢. 在胰岛中，葡萄糖对 细胞内钙和分泌。 葡萄糖的稳态效应 是诱导细胞内钙的节律性振荡， 电位，但葡萄糖的最早作用是降低 钙离子浓度 酵母己糖激酶转基因小鼠的建立 新生儿胰岛缺乏胰岛素分泌， 是由泌乳素分泌的胰岛引起的 我们还开发了 一种潜在的治疗囊性纤维化的药物， A1受体拮抗剂，8-环戊基-1，3-二丙基黄嘌呤激活 人上皮细胞和小鼠成纤维细胞系的氯流出 携带CFTR（Δ F508）突变但不携带野生型CFTR。 我们 我还了解到阿尔茨海默病淀粉样蛋白形成离子 通道的双层膜，这种活动可能是基础 淀粉样蛋白神经毒性