Mechanisms of glycine receptor modulation by ethanol

乙醇调节甘氨酸受体的机制

• 批准号: 6876161
• 负责人: Michael Thomas Roberts
• 金额: $ 2.81万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-12-01 至 2005-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6876161
• 关键词: anesthetics; conformation; dosage forms; electrophysiology; ethanol; glycine receptors; mutant; neuropharmacology; neurotransmitters; predoctoral investigator; protein structure function; site directed mutagenesis; tissue /cell culture; voltage /patch clamp

DESCRIPTION (provided by applicant): Glycine Receptors (GlyRs) play a significant role in mediating the in vivo responses to ethanol exposure. Despite numerous studies characterizing the direct effects of ethanol on GlyRs, the molecular mechanisms of ethanol modulation of GlyR function remain unknown. We propose to use patch clamp electrophysiology to investigate the effects of ethanol on the single-channel properties of GlyR function. A mutant alphal GlyR (D97R) that spontaneously cycles between closed, open, and desensitized states in the absence of neurotransmitter will allow us to directly probe ethanol effects on GIyR activity while removing the neurotransmitter binding and unbinding variables that confound most studies of ligand-gated ion channel modulation. The proposed experiments will test the hypothesis that ethanol and related compounds, including a number of inhalants and volatile anesthetics, modulate GlyR function by stabilizing the receptor open conformation. An understanding of the molecular mechanisms of alcohol action will aid in the rational development of pharmaceuticals to treat alcoholism.

描述（由申请人提供）：甘氨酸受体（GlyR）在介导体内对乙醇暴露的反应中发挥着重要作用。尽管大量研究描述了乙醇对 GlyR 的直接影响，但乙醇调节 GlyR 功能的分子机制仍然未知。我们建议使用膜片钳电生理学来研究乙醇对 GlyR 功能单通道特性的影响。在没有神经递质的情况下，突变体 alphal GlyR (D97R) 可在关闭、开放和脱敏状态之间自发循环，这将使我们能够直接探测乙醇对 GlyR 活性的影响，同时消除神经递质结合和解除结合变量，这些变量使大多数配体门控研究感到困惑。离子通道调制。拟议的实验将检验乙醇和相关化合物（包括许多吸入剂和挥发性麻醉剂）通过稳定受体开放构象来调节 GlyR 功能的假设。了解酒精作用的分子机制将有助于合理开发治疗酒精中毒的药物。