MOLECULAR BASIS OF LIGAND-NA+ CHANNEL INTERACTIONS

配体-NA 通道相互作用的分子基础

• 批准号: 3288083
• 负责人: GING K WANG
• 金额: $ 16.94万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-09-06 至 1993-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3288083
• 关键词: acidity /alkalinity; bioenergetics; biological transport; chemical binding; chemical structure function; conformation; ligands; local anesthetics; membrane model; physical chemical interaction; sodium channel; tissue /cell culture; transport proteins; voltage /patch clamp

The goal of this project is to understand better the molecular mechanism of dynamic interactions between the voltage-gated Na channel and specifically bound ligands. Among these ligands are local anesthetic (L.A.) drugs which inhibit the Na currents and alpha- and beta- scorpion toxins which modify primarily the channel inactivation and activation gating process respectively. The Na channel is an extremely dynamic protein which exhibits rapid time- and voltage- dependent conformational changes upon depolarization. Channel-specific ligands interfere with these structural rearrangements and thus are potential probes for the ligand binding sites and their corresponding functions. In this proposal, we plan to examine the ion pathway and gating property of the ligand-bound Na channel in muscle and heart cells using planar lipid bilayer and/or patch-clamp techniques. The action of the L.A. drug appears to be strongly modulated by voltage, Na+ ions, and pH as outlined in Hille's modulated receptor hypothesis. In his model, the receptor conformation is changed upon depolarization and accordingly, the receptor-ligand binding is altered. At present, the physico-chemical properties of the L.A. receptor and the molecular basis of its modulation remain largely unknown. Toward this understanding, we will determine the number of L.A. receptors within the Na channel, the mechanism of receptor modulation, as well as the structure-activity relationship of L.A. drugs. Beside L.A. drugs, we also plan to use alpha- and beta-scorpion toxins to examine their separate "external" binding sites. These peptide toxins are ideal tools for characterizing the activation and inactivation processes influenced by external Na channel structure. In turn, scorpion toxins may later be applied to relate the inactivation or activation gating process to the L.A. action. Together, these studies should provide us an integrated view of ligand-Na channel interactions.

这个项目的目标是更好地了解 电压门控性钠离子通道之间的动态相互作用机制 通道和特异性结合的配体。 在这些配体中， 局部麻醉药（L.A.）抑制钠电流的药物， α-和β-蝎毒素主要改变 通道失活和激活门控过程。 Na通道是一种非常动态的蛋白， 快速的时间和电压依赖性构象变化， 去极化 细胞特异性配体干扰这些 结构重排，因此是潜在的探针 配体结合位点及其相应的功能。 在这 建议，我们计划检查离子路径和门控属性 肌肉和心脏细胞中配体结合的Na通道的研究， 平面脂质双层和/或膜片钳技术。 的作用 洛杉矶 药物似乎受到电压、Na+ 离子和pH，如Hille的调节受体假说中所概述的。 在他的模型中，受体构象在 去极化，因此，受体-配体结合是 改变了 目前，对L.A. 受体及其调节的分子基础在很大程度上仍然是 未知 为了理解这一点，我们将确定 洛杉矶数 钠通道内的受体，机制 受体调节，以及结构-活性 洛杉矶的关系 毒品 除了洛杉矶药物，我们还计划使用 α-和β-蝎毒素来检查它们各自的 “外部”结合位点。 这些肽毒素是理想的工具， 表征活化和失活过程 受外部Na通道结构的影响。 反过来，蝎子 毒素可随后应用于与灭活或 启动门控程序 行动上 所有这些 研究应该为我们提供一个配体-钠通道的综合观点 交互.