INHALED AMESTHETICS: MOLECULAR ACTIONS ON ION CHANNELS

该项目将使用重组离子通道来确定 吸入麻醉剂在过去的资助周期中，该项目展示了多种麻醉剂 作用于几种离子通道，特别是A型γ-氨基丁酸（GABAA）和甘氨酸受体。这些研究促进并帮助了Homanics博士构建突变小鼠，随后Sonner和埃格博士对其进行了体内表征。结果说明了多学科方法的实用性，并揭示了麻醉作用的复杂性。虽然麻醉剂以合理的方式影响许多蛋白质靶点来解释麻醉，但每个靶点的相对重要性尚不清楚。这些结果促使了对包括甘氨酸和N-甲基-D-天冬氨酸（NMDA）受体以及特异性钠通道在内的多个靶点的研究。我们将修改这些受体和通道，以提供有关机制的信息，包括提供其他离子载体的检查模板。我们建议，吸入麻醉剂结合，从而侵占，由离子通道的跨膜区域形成的充满水的空腔。如果腔容积严重影响通道门控，则腔中存在麻醉剂将改变通道功能。具体来说，我们假设对甘氨酸、NMDA和一些电压激活钠通道的作用介导麻醉剂的主要作用，并且更全面地理解麻醉需要检查对这些通道作用的分子机制，以及新的分子和遗传工具， 这些通道在体内的研究。

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.