GENERAL ANESTHETIC MECHANISMS IN EXCITABLE MEMBRANES

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This aim of this project is to investigate the molecular mechanisms of action of general anesthetics on ligand-gated ion channels. Despite decades of study by many investigators, the mechanisms by which general anesthetics produce unconsciousness are unknown. Ion channels of excitable membranes in general and ligand-gated ion channels in particular are likely "targets" of anesthetic drugs. However, whether the drugs act directly on these membrane proteins or exert their effects indirectly, through the lipid bilayer of the cell membrane, remains unclear. The electrophysiological technique of single channel recording provides direct information about the behavior of ion channels at the molecular level and is well suited to the study of mechanisms of drug action. We will use conventional single channel recording techniques and a novel method for rapid drug application. The effects of volatile anesthetics (e.g. isoflurane), barbiturates (e.g. pentobarbital) and other anesthetics (e.g. ketamine) on ligand-gated ion channels (acetlycholine receptor-channels, NMDA-activated channels , GABA receptor-channels and calcium-activated potassium channels) will be examined. The adequacy of models of anesthetic action (e.g. membrane fluidity, channel block and allosteric binding) will be tested. The variety of anesthetics and ion channels chosen permits a search for generalities in anesthetic-ion channel interactions. The long term goal is to discriminate among competing theories of anesthetic action.