MECHANISMS OF ANESTHETIC ACTION ON SIGNAL TRANSDUCTION

麻醉对信号传导的作用机制

• 批准号: 2184984
• 负责人: GABOR SZABO
• 金额: $ 32.82万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-05-01 至 1997-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2184984
• 关键词: G protein; anesthesia; biological signal transduction; cell membrane; lipid bilayer membrane; membrane channels

The overall objective of this Research Program is to elucidate the molecular mechanisms by which anesthetics manifest their pharmacological and physiological effects. Small lipophilic molecules of widely divergent chemical structures may exhibit similar anesthetic properties, suggesting a general mechanism through interference with key cellular communication processes. This leads us to the specific hypothesis that anesthetic action may be attributed to the perturbation of signal transduction processes associated with cell membranes. An integrated, collaborative and multidisciplinary approach will be used to test various aspects of this basic hypothesis. The action of anesthetics will be studied from the standpoint of membrane physical chemistry (Projects 0001 and 0002), G protein mediated signal transduction (Projects 0002 and 0003), and ion channel electrophysiology (Projects 0003 and 0004). The multidisciplinary approach, including clinical expertise, will ensure that realistic and useful objectives are set, pursued efficiently using the most appropriate methodologies, and applied rapidly to develop an improved understanding of the cellular and molecular mechanisms of anesthetic action. Four faculty members from the departments of Anesthesiology, Biochemistry, Chemistry, and Physiology are collaborating on 4 projects focused on the effects of anesthetics on: (1) membrane physical and electrostatic properties, (2) G- protein receptor interactions, (3) G-protein coupled channel regulation, and (4) Ca2+ release channel kinetics modulation of the action of anesthetics on the Na+ channel. These projects will concentrate on a common group of anesthetics selected for their chemical diversity in order to establish characteristic patterns for the anesthetic sensitivity of transmembrane signaling. By comparing these to the anesthetic sensitivity of salient physiological processes, the proposed studies should identify significant primary and/or secondary effects of anesthetics that are produced by interference with specific signal transduction pathways. Elucidation of the relationships among various molecular structures and their mode of anesthetic action should ultimately lead to practical advances in anesthesiology by guiding the design of molecules with improved clinical properties and by leading to a better understanding and application of potentially synergistic or complementary agents and techniques.

该研究计划的总体目的是阐明 麻醉药表现出其药理的分子机制 和生理影响。 较小的亲脂分子 化学结构可能表现出相似的麻醉特性，表明 通过干扰关键细胞通信的一般机制 过程。 这使我们提出了一个麻醉作用的特定假设 可能归因于信号转导过程的扰动 与细胞膜有关。 一个综合，协作和 多学科方法将用于测试此的各个方面 基本假设。 麻醉剂的作用将从 膜物理化学的角度（项目0001和0002），G 蛋白质介导的信号转导（项目0002和0003）和离子 通道电生理学（项目0003和0004）。 多学科 包括临床专业知识在内的方法将确保现实和 设定有用的目标，使用最合适的 方法论，并迅速应用以提高对 麻醉作用的细胞和分子机制。 四个教师 麻醉，生物化学，化学，化学，化学部门的成员 生理学正在与4个专注于的4个项目合作 麻醉药：（1）膜的物理和静电特性，（2）g- 蛋白受体相互作用，（3）G蛋白偶联通道调节， （4）CA2+释放通道动力学调制的作用 NA+通道上的麻醉药。 这些项目将集中于 为其化学多样性选择的通用麻醉剂组 建立特征模式的麻醉灵敏度 跨膜信号传导。 通过将它们与麻醉灵敏度进行比较 在显着的生理过程中，拟议的研究应确定 麻醉药的重要主要和/或次要作用 通过干扰特定信号转导途径产生。 阐明各种分子结构之间的关系和 他们的麻醉作用方式最终应导致实用 通过指导分子的设计改进，麻醉学的进步 临床特性，并导致更好的理解和 应用潜在的协同或互补代理以及 技术。