INHALED AMESTHETICS: MOLECULAR ACTIONS ON ION CHANNELS

该项目将使用重组离子通道来定义分子作用部位 吸入麻醉剂。在过去的赠款周期中，该项目展示了多种麻醉剂 对几种离子通道的作用--特别是A型γ-氨基丁酸(GABAA)和甘氨酸受体。这些研究促使并帮助Homanics博士构建了突变小鼠，Sonner和Eger博士随后在体内确定了这些突变小鼠的特征。这些结果说明了多学科方法的实用性，并揭示了麻醉行为的复杂性。尽管麻醉剂以合理的方式影响许多蛋白质靶点，以解释麻醉，但每个靶点的相对重要性尚不清楚。这些结果促使了对多靶点的研究，包括甘氨酸和N-甲基-D-天冬氨酸(NMDA)受体，以及特定的钠通道。我们将修改这些受体和通道，以提供有关机制的信息，包括提供用于检查其他离子载体的模板。我们认为吸入麻醉剂结合在离子通道跨膜区形成的充满水的空腔内，并因此侵蚀这些空腔。如果腔体积严重影响通道门控，则腔内麻醉剂的存在将改变通道功能。具体地说，我们假设对甘氨酸、nmda和一些电压激活的钠通道的影响介导了麻醉剂的主要作用，而对麻醉的更全面的理解需要检查这些通道上的分子作用机制，以及新的分子和遗传工具。 在活体内对这些通道的研究。

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.