MOLECULAR PHARMACOLOGY OF ANESTHETICS IN C ELEGANS

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The long term goal of this study is to understand the molecular basis of action of volatile anesthetics. Little is known about how volatile anesthetics produce reversible unconsciousness; this is true of our understanding at either the gross anatomical or subcellular/molecular level. This proposal uses a molecular genetic approach to try to understand the mechanism of action of volatile anesthetics in C.elegans. The completely defined neuroanatomy and extensive genetic analysis of C.elegans make it an attractive, simple, model system. In addition, we have identified two uncoordinated mutants that differ greatly from the wild type worm in their sensitivity to the most potent volatile anesthetics. Their behavior indicates a change at the site of anesthetic action. These mutant strains, unc-79 and unc-80, can each behave normally in anesthetics when combined with other mutations, unc-9 or unc-7. We plan to use these mutations to understand the molecular nature of the site of anesthetic action. The specific aims of this proposal are: 1) To characterize the genetic control of anesthetic response in C.elegans by isolating additional alleles of unc-79, unc-80, unc- 9 and unc-7. New mutations will also be sought that confer hypersensitivity or resistance to different anesthetics. 2) To construct animals that are genetic mosaics for either unc- 79 or unc-9 or unc-7, and thus pinpoint the effects of each of these genes to specific cell lineages, or to specific tissues. 3) To clone unc-79 and unc-80 by a transposon tagging technique. We will also attempt to clone unc-79 by means of mutant rescue. We plan to analyze the primary structure of the corresponding protein products, and search for homologous protein products in more complex organisms. Determining the components of the site of action of volatile anesthetics is the first step in studying the mechanism of action of these agents. Defining the molecular mechanism of action of volatile anesthetics in a relatively simple organism, C.elegans, may identify very basic processes that underlie the production of unconsciousness in other species. Such knowledge may be crucial in future attempts to synthesize volatile anesthetic agents with the specificity now seen, for example, emerging in narcotic therapy.