VOLATILE ANESTHETIC ACTIONS--MOLECULAR GENETIC ANALYSIS

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The volatile, lipophilic compounds used to produce general anesthesia during surgery have direct effects on all cells and tissues that have been carefully examined. However, the mechanism(s) and primary site(s) of action of these anesthetics in any cell or tissue are unknown. The long- range objective of this work is to characterize cellular target(s) of volatile anesthetics and response(s) elicited by these compounds. These will be done in the model eukaryotes Saccharomyces cerevisiae (yeast), in which it is possible to use powerful molecular genetic tools for these studies. We have shown that volatile anesthetics inhibit yeast growth and that the action of these compounds as yeast growth inhibitors parallels their actions as agents for inducing anesthesia. Thus, a premise underlying these studies is that identification of the mechanism(s) of action of anesthetics in yeast should provide fundamental insight into at least some of the actions of these compounds in mammalian cells. Our results indicate that both amino acid transport and ubiquitination play key roles in anesthetic response of yeast. Our working hypotheses suggest that ubiquitination of a ubiquitination-dependent process involving cellular permeases is critical for this response. The specific aims of the work in this application are: 1)Characterization of effects of anesthetics on ubiquitin metabolism. Mutations in any of several genes that have been implicated in ubiquitin metabolism alter the response of yeast to volatile anesthetics. 2) Characterization of effects of anesthetics on nutrient transport. Several lines of evidence from our laboratory indicate that amino acid transport plays a critical role in the volatile anesthetic response of yeast.