MECHANISMS OF ANESTHETIC ACTION ON SIGNAL TRANSDUCTION

麻醉对信号传导的作用机制

• 批准号: 3096428
• 负责人: GABOR SZABO
• 金额: $ 48.61万
• 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/3096428
• 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标是阐明 麻醉剂发挥其药理作用的分子机制 和生理效应。 不同亲脂性小分子 化学结构可能表现出相似的麻醉特性，表明 通过干扰关键蜂窝通信的通用机制 流程。 这使我们得出一个具体的假设：麻醉作用 可能归因于信号转导过程的扰动 与细胞膜有关。 一个综合性、协作性和 将使用多学科方法来测试该项目的各个方面 基本假设。 麻醉药的作用将从以下方面进行研究： 膜物理化学的观点（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 方法，包括临床专业知识，将确保现实和 设定有用的目标，并使用最合适的方法有效地追求 方法论，并迅速应用以加深对 麻醉作用的细胞和分子机制。 四个教员 来自麻醉科、生物化学科、化学科的成员， 和生理学正在合作开展 4 个项目，重点关注 麻醉剂对：(1) 膜物理和静电特性，(2) G- 蛋白质受体相互作用，(3) G 蛋白偶联通道调节， (4) Ca2+释放通道动力学调节作用 Na+ 通道上的麻醉剂。 这些项目将集中于 因其化学多样性而选择的常见麻醉剂组 建立麻醉敏感性的特征模式 跨膜信号传导。 通过将这些与麻醉敏感性进行比较 对于显着的生理过程，拟议的研究应确定 麻醉剂的显着主要和/或次要影响是 通过干扰特定的信号转导途径而产生。 阐明各种分子结构之间的关系 他们的麻醉作用方式最终应该导致实际的结果 通过指导改进的分子设计来推动麻醉学的进步 临床特性并通过导致更好的理解和 应用潜在的协同或互补剂，以及 技术。