MOLECULAR BASIS OF LIGAND-NA+ CHANNEL INTERACTIONS

配体-NA 通道相互作用的分子基础

• 批准号: 3288082
• 负责人: GING K WANG
• 金额: $ 16.75万
• 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/3288082
• 关键词: acidity /alkalinity; 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.

该项目的目标是更好地了解分子 电压门控Na之间的动态相互作用机制 通道和特异性结合的配体。 这些配体包括 局部麻醉 (L.A.) 药物可抑制钠电流和 α-和β-蝎子毒素主要改变 通道失活和激活门控过程分别。 Na通道是一种极其动态的蛋白质，它表现出 快速的时间和电压依赖性构象变化 去极化。 通道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。 在这个 建议，我们计划检查离子通道和门控特性 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。 的行动 洛杉矶药物似乎受到电压 Na+ 的强烈调节 Hille 的调节受体假说中概述了离子和 pH 值。 在他的模型中，受体构象发生变化 去极化，因此，受体-配体结合是 改变了。 目前，L.A. 的物理化学特性。 受体及其调节的分子基础在很大程度上仍然存在 未知。 为了实现这一理解，我们将确定 Na 通道内 L.A. 受体的数量，其机制 受体调节以及结构活性 洛杉矶毒品的关系。 除了洛杉矶药物之外，我们还计划使用 α-和β-蝎子毒素来检查它们的分离 “外部”结合位点。 这些肽毒素是理想的工具 表征激活和失活过程 受外部Na通道结构的影响。 反过来，蝎子 随后可以应用毒素来关联失活或 L.A. 行动的激活门控过程。 在一起，这些 研究应该为我们提供配体-Na通道的综合观点 互动。