Genetics and the Mechanisms of Action of Inhaled Anesthetics

Louise   M.   Steele; Phil   G.   Morgan; Margaret   M.   Sedensky

Abstract

Inhaled anesthetics have been used for more than a century, and they are currently administered to millions of patients each year. Although well understood in an empirical sense, their basic molecular mechanisms of action are still unknown. During the past two decades, a large amount of evidence has been presented that is most consistent with the hypothesis that inhaled anesthetics act at multiple sites. For example, genetic mutations exist that distinguish between different inhaled anesthetics, i.e. the mutations alter sensitivity to some anesthetics differently than others. Since it is probable that multiple mechanisms contribute to inhaled anesthetic action, a genetic approach is a powerful method for sorting out which molecules are involved in specific anesthetic effects. This review describes recent pharmacogenetic studies performed using model organisms, including yeast, nematodes, fruit flies, and mice. At first glance, the results of these studies are notable for their lack of a common putative molecular target. In fact, the results suggest that anesthetics interact with a seemingly broad range of cellular components including ion channels, membrane receptors, lipid rafts, and the mitochondrial electron transport chain. However, a unifying theme is beginning to emerge, one that implicates the presynaptic neuron as a common functional target for inhaled anesthetics. Intriguing similarities among the results suggest that many of the findings obtained in model organisms can be generalized across disparate phyla, and that the findings will be applicable in humans. By continuing to exploit the power of genetics, such studies are likely to unravel the great mystery of how inhaled anesthetics produce their effects.

Keywords: Yeast, TAT1, general amino acid control (GCN) pathway, Lipid Rafts, unc-79, Drosophila melanogaster

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