Mechanism of Action of Volatile Inhaled Anesthetics

Volatile anesthetics are indispensable for modern medical practice. Despite more than 150 years of determined investigation, the sites and mechanisms of action of these clinically essential drugs remain unknown. We are using molecular genetic studies in the simple eukaryote Saccharomyces cerevisiae (yeast) to investigate the cellular activities of these compounds. We find that volatile anesthetics inhibit yeast growth and that there are striking parallels between the activity of these compounds as yeast growth inhibitors and as mammalian anesthetics. These parallels include: rapid and reversible effects; very sharp dose-response curve; direct correlation between potency and lipophilicity; mixtures of different anesthetics are additive in their effects; and lipophilic compounds that are nonanesthetic in mammals do not affect yeast. These similarities suggest that identification of targets or mechanisms of action of volatile anesthetics in yeast will provide insight into the activity of these drugs in mammals. Molecular genetic analysis of yeast mutants with altered anesthetic sensitivity indicates that ubiquitin metabolism plays a key role in the response of yeast to these drugs. Support for this conclusion comes from finding that mutation of ubiquitin ligase or of proteasome subunits alters the anesthetic sensitivity of yeast. In addition, yeast mutants with decreased levels of ubiquitin are resistant to volatile anesthetics. Our present studies involve investigating the role of ubiquitin metabolism in normal cellular response to these drugs.