INHALED AMESTHETICS: MOLECULAR ACTIONS ON ION CHANNELS

吸入美容剂：离子通道上的分子作用

• 批准号: 6807222
• 负责人: Robert A Harris
• 金额: $ 20.58万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6807222
• 关键词: NMDA receptors; Xenopus oocyte; body movement; brain; chemical binding; electrophysiology; genetically modified animals; genotype; glutamate receptor; glycine receptors; inhalation anesthesia; ionophores; isoflurane; laboratory mouse; membrane channels; molecular site; neurotransmitter receptor; pharmacokinetics; receptor binding; receptor expression; site directed mutagenesis; sodium channel; spinal cord; voltage /patch clamp; water

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.

该项目将使用重组离子通道来定义分子作用位点 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 对多种离子通道的作用，特别是 A 型 γ-氨基丁酸 (GABAA) 和甘氨酸受体。这些研究促进并帮助 Homanics 博士构建了突变小鼠，随后由 Drs. Homanics 对其进行了体内表征。桑纳和埃格尔。结果说明了多学科方法的实用性并揭示了麻醉操作的复杂性。尽管麻醉剂以合理解释麻醉的方式影响许多蛋白质靶点，但每个靶点的相对重要性尚不清楚。这些结果促使人们对包括甘氨酸和 N-甲基-D-天冬氨酸 (NMDA) 受体以及特定钠通道在内的多个靶点进行研究。我们将修改这些受体和通道以提供有关机制的信息，包括提供用于检查其他离子载体的模板。我们建议吸入麻醉剂结合并从而侵入由离子通道跨膜区域形成的充满水的空腔。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。具体来说，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，并且对麻醉的更全面的了解需要检查这些通道的分子作用机制，以及新的分子和遗传工具 体内这些通道的研究。