MECHANISMS OF ANESTHETIC ACTION ON SIGNAL TRANSDUCTION

本研究计划的总体目标是阐明 麻醉剂表现其药理学作用的分子机制 和生理效应。 小的亲脂性分子， 化学结构可能表现出类似的麻醉特性，这表明 通过干扰关键蜂窝通信的一般机制 流程. 这使我们得出一个特定的假设， 可能归因于信号转导过程的扰动 与细胞膜相关。 一个综合、协作和 多学科的方法将用于测试这一点的各个方面 基本假设 麻醉剂的作用将从 膜物理化学的观点（0001和0002项目），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 制定有用的目标，并使用最合适的方法有效地追求目标。 方法，并迅速加以应用， 麻醉作用的细胞和分子机制。 四系 来自麻醉科、生化科、化学科、 和生理学正在合作4个项目，重点是 麻醉剂对：（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， （4）Ca ~（2+）释放通道动力学调节 钠离子通道的麻醉剂。 这些项目将集中在一个 根据其化学多样性选择的一组常见麻醉剂， 建立麻醉敏感性的特征模式， 跨膜信号 通过对比麻醉剂的敏感性 的显着生理过程，拟议的研究应确定 麻醉剂的显著主要和/或次要作用， 通过干扰特定的信号转导途径产生。 阐明了各种分子结构之间的关系， 它们的麻醉作用模式最终会导致 麻醉学的进展，通过指导分子的设计， 临床特性，并导致更好的理解和 潜在的协同或互补剂的应用， 技术.

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.