Molecular mechanisms of volatile anesthetic response in Saccharomyces cerevisiae

Although volatile anesthetics are absolutely essential for modern medical practice, their sites and mechanisms of action remain elusive. While many effects of these agents have been characterized, clear insight into how these effects relate to the physiological state of anesthesia have not been established. Understanding the cellular basis of anesthetic response may allow for the design of safer compounds that induce anesthesia without causing the many undesirable side effects associated with these agents. In an effort to determine physiologically relevant anesthetic targets and cellular mechanisms affected by these agents, molecular genetic investigations using the yeast Saccharomyces cerevisiae have been conducted. The parallel manner in which volatile anesthetics affect yeast growth and induce mammalian anesthesia suggests identification of biologically relevant targets or mechanisms of action in yeast should provide insights into the activities of these drugs in mammals.; Analyses of yeast mutants altered in their response to volatile anesthetics showed these agents affect the ability of yeast to import critical nutrients, in particular leucine and tryptophan, from the external environment. This inhibition of amino acid import is most likely a result of direct inhibition of specific amino acid permeases. A consequence of nutrient limitation in yeast is activation of nutrient-sensing signaling pathways that regulate gene expression and affect protein synthesis. One of these pathways, the general amino acid control (GCN) pathway, affects phosphorylation of the translation initiation factor eIF-2α, leading to an overall decrease in protein translation. It was shown that anesthetics induce eIF-2α phosphorylation in yeast, suggesting a role for this pathway in volatile anesthetic response. However, the time-course for this induction indicates the GCN pathway is most likely involved in long-term maintenance of growth inhibition rather than in the initial inhibitory response. Because nutrient-sensing signaling pathways are conserved from yeast to man, these studies provide testable hypotheses for actions of volatile anesthetics in more complex eukaryotes.