This project will use recombinant ion channels to define the molecular sites of action of inhaled anesthetics. During the past grant cycle, the project demonstrated diverse anesthetic actions on several ion channels--in particular, type A gamma-aminobutyric acid (GABAA) and glycine receptors. The studies prompted and aided Dr. Homanics' construction of mutant mice that were subsequently characterized in vivo by Drs. Sonner and Eger. The results illustrate the utility of a multidisciplinary approach and reveal the complexity of anesthetic actions. Although anesthetics affect many protein targets in ways that plausibly explain anesthesia, the relative importance of each target is not known. Such results prompt the proposed studies of multiple targets including glycine and N-methyI-D-aspartate (NMDA) receptors, and specific sodium channels. We will modify these receptors and channels to provide information on mechanisms, including provision of templates for examination of other ionophores. We propose that inhaled anesthetics bind in, and thereby encroach upon, water-filled cavities formed by transmembrane regions of ion channels. If the cavity volume critically affects channel gating, the presence of anesthetic in the cavity will alter channel function. Specifically, we hypothesize that effects on glycine, NMDA, and some voltage-activated sodium channels mediate primary effects of anesthetics, and that a fuller understanding of anesthesia requires examination of molecular mechanisms of action on these channels, as well as new molecular and genetic tools for the study of these channels in vivo.
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