MECHANISMS OF ANESTHETIC ACTION ON SIGNAL TRANSDUCTION

本研究计划的总体目标是阐明 麻醉药发挥药理作用的分子机制 以及生理效应。广泛分散的亲脂小分子 化学结构可能表现出类似的麻醉特性，这表明 干扰关键蜂窝通信的一般机制 流程。这就引出了一个具体的假设，即麻醉作用 可能归因于信号转导过程的扰动 与细胞膜相关的。集成、协作和 将使用多学科方法来测试这一点的各个方面 基本假设。麻醉剂的作用将从 膜物理化学观点(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)。多学科的 方法，包括临床专业知识，将确保现实和 设定有用的目标，并使用最适当的方法有效地实现这些目标 方法论，并迅速应用于发展对 麻醉作用的细胞和分子机制。四名教职员工 麻醉学、生物化学、化学系、 和生理学正在合作4个项目，重点是 麻醉药：(1)膜的物理和静电性质，(2)G- 蛋白受体相互作用，(3)G蛋白偶联通道调节， 和(4)钙离子释放通道动力学的调控作用 钠离子通道上的麻醉剂。这些项目将集中在 按化学多样性顺序选择的麻醉药的常见类别 建立麻药敏感性的特征模式 跨膜信号。通过将这些与麻醉敏感性进行比较 在显著的生理过程中，拟议的研究应该确定 麻醉药的显著主要和/或继发性影响是 通过干扰特定的信号转导通路而产生。 阐明不同分子结构和结构之间的关系 他们的麻醉作用模式最终应该导致实际 用改进的分子设计方法指导麻醉学的研究进展 临床特征，并通过导致更好的理解和 潜在的增效剂或补充剂的应用 技巧。

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.