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.
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