Mechanism of Action of Volatile Anesthetics

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DESCRIPTION (provided by applicant): Despite a great deal of research, no studies have yielded a definitive molecular picture of a site of action of volatile anesthetics. However, volatile anesthetics appear to disrupt a very fundamental process of neuronal function, one that appears to be highly conserved across many disparate phyla. Such a basic function is best suited to genetic analysis in a simple animal model with later extension into more complicated organisms. For this reason, we are using C. elegans as an animal model in which to define molecular components of anesthetic sites of action. We have isolated mutations in several genes in C. elegans that control sensitivity to an array of gaseous anesthetics. Our results indicate that the gene unc-1 codes for a protein that is a component of at least one such site of action for volatile anesthetics. We have cloned and characterized the unc-1 gene from C. elegans. unc-1 codes for a close homologue of the mammalian protein, stomatin, which is important in controlling ion flux across cell membranes. Other data indicates that unc-1 may exert its effect on anesthetic response by interacting with membrane microdomains called lipid rafts. We have shown that lipid rafts exist in C. elegans and that UNC-1 is associated with these rafts. A wide array of proteins affecting cell physiology have been shown to be associated with lipid rafts. Unc-1 is expressed at all postembryonic times in C. elegans, primarily in the nervous system. The UNC-1 protein interacts with a sodium channel and a novel G-protein coupled receptor to control anesthetic sensitivity. Homologues of each of these proteins are part of a stomatin-related protein complex affected by volatile anesthetics. The specific aims of this project are: 1. To characterize more fully the stomatin-related complex controlling anesthetic sensitivity in C. elegans. 2. To characterize lipid rafts from C. elegans. The association of other proteins with these micro domains will then be studied. 3. To measure the effects of anesthetics on stomatin deficient mice. This approach is the logical extension of the successful use of a model system such as C. elegans to demonstrate its applicability to mammals.