NUTRITIONAL REGULATION OF THE GUANYLIN/STA RECEPTOR

鸟苷酸/STA 受体的营养调节

• 批准号: 2391455
• 负责人: Lawrence Scheving
• 金额: $ 17.31万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-04-08 至 1999-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2391455
• 关键词: SDS polyacrylamide gel electrophoresis; autoradiography; biological signal transduction; biological transport; brush border membrane; chromaffin cells; circadian rhythms; diarrhea; enterotoxins; enzyme activity; enzyme biosynthesis; fasting; gastrointestinal system; guanylate cyclase; hormone receptor; intracellular transport; laboratory rat; northern blottings; nutrition; nutrition related tag; peptide hormone

Guanylyl cyclase C (GC-C) is a receptor-enzyme that is the major source of cyclic GMP at the brush border surface of the intestinal epithelial cell. GC-C has an extracellular ligand binding domain. Ligand binding activates an intracellular enzyme domain, ultimately leading to the opening of the cystic fibrosis transmembrane regulator (CFTR) chloride channels. GC-C can bind two different ligands. It can bind the STa enterotoxins produced by Escherichia coli and other diarrhetic bacteria. These toxins are a major cause of infant and travelers diarrhea world-wide. It can also bind the newly discovered intestinal peptide, guanylin, which is produced by enterochromaffin (EC) cells. Guanylin resembles the circulating natriuretic peptides (i.e., atrial natriuretic peptide -- ANP) in its precursor-product relationship, receptor structure, and activation of guanylate cyclase. Because guanylin and ST have the same receptor, the profuse diarrhea caused by the STa toxin is probably due to the unregulated activation of GC-C. Production of cyclic GMP at the brush border surface is associated with increased chloride secretion and decreased absorption, consistent with the secretory diarrhea associated with the STa toxin. However, the role of GC- C in normal intestinal physiology is unclear. Very little is known about the biology of GC-C and its natural ligand, guanylin. Yet the guanylin-STa receptor effector system may regulate enteric electrolyte balance or water loss, seeing as an intestinal counterpart to the brain and atrial natriuretic peptide systems. Further, the synthesis or activation of guanylin and GC-C may be controlled by the intestinal response to dietary factors, such as stretch, osmotic, or hormonal stimuli. The long term goal of the proposed research is to understand the guanylin- receptor interaction and its mechanisms of cell signaling using both biochemical and molecular approaches. Understanding the structure and function of this receptor system may contribute to the design of new anti- diarrheal drugs, vaccines or intestinal modulators. Because the rat intestinal response to STa is heightened by as much as ten-fold during starvation and because STa-associated secretory diarrhea is exacerbated in famished individuals, we will focus on this receptor system in the fasted rat. The specific aims of this proposal are as follows: (l) To determine the dietary and circadian regulation of GC-C and GN at different intestinal sites. (2) To determine the molecular basis for the abrupt GC-C down- regulation from the enterocyte brush border surface that occurs when fasted rats are refed. (3) To define the localization and movement of GC-C during its synthesis, assembly, and transport to the brush border and after its binding to the STa toxin.

鸟苷酸环化酶C(GC-C)是一种受体-酶，它是鸟苷酸的主要来源。 位于肠上皮细胞刷状缘面的环状GMP。 GC-C有一个胞外配体结合域。配体结合被激活 一个细胞内的酶结构域，最终导致开放的 囊性纤维化跨膜调节剂(CFTR)氯通道。GC-C可以 结合两种不同的配体。它能结合沙门氏菌产生的肠毒素。 大肠杆菌和其他腹泻细菌。这些毒素是主要的 全球婴儿和旅行者腹泻的原因。它还可以将 新发现的肠肽鸟苷素，由 肠嗜铬细胞。鸟语林类似于循环 ITS中的利钠肽(即心钠素) 前体-产物关系、受体结构和激活 鸟苷环化酶。因为鸟苷素和ST有相同的受体，所以 StA毒素引起的大量腹泻可能是由于 GC-C的非调控激活。 在刷子边界表面产生环状GMP与 氯化物分泌增加，吸收减少，与 与StA毒素相关的分泌性腹泻。然而，GC的作用- C在正常肠道生理中的作用尚不清楚。人们对此知之甚少 GC-C及其天然配体鸟苷的生物学研究。然而观音台 受体效应系统可能调节肠道电解质平衡或水分 损失，被视为大脑和心房的肠道对应 利钠肽系统。此外，合成或激活 鸟苷素和GC-C可能受肠道对饮食的反应控制 因素，如伸展、渗透或荷尔蒙刺激。 拟议研究的长期目标是了解鸟语素- 二者在细胞信号转导中的相互作用及其机制 生物化学和分子方法。了解其结构和 该受体系统的功能可能有助于设计新的抗肿瘤药物。 止泻药、疫苗或肠道调节剂。因为老鼠 肠道对沙门氏菌的反应在 饥饿，因为STA相关的分泌性腹泻在 饥饿的人们，我们将关注禁食中的这个受体系统 老鼠。 这项建议的具体目的如下：(L)确定 不同肠道中GC-C和GN的饮食和昼夜节律调节 网站。(2)确定GC-C突然下降的分子基础- 从肠上皮细胞刷毛边缘表面发生的调节 禁食的大鼠被重新喂食。(3)明确GC-C的定位和移动 在合成、组装和传输到笔刷边界的过程中 在它与StA毒素结合后。