Mechanisms of glycine receptor modulation by ethanol

描述(由申请人提供)：甘氨酸受体(GlyRs)在调节体内对乙醇暴露的反应中发挥着重要作用。尽管大量研究表明乙醇对GlyR的直接影响，但乙醇调节GlyR功能的分子机制仍不清楚。我们建议使用膜片钳电生理学来研究乙醇对GlyR功能的单通道特性的影响。一个突变的Alphal GlyR(D97R)在没有神经递质的情况下会自发地在闭合、开放和不敏感状态之间循环，这将使我们能够直接探讨乙醇对GIyR活性的影响，同时消除神经递质结合和解离变量，这些变量混淆了大多数配基门控离子通道调节的研究。拟议的实验将检验这样一个假设，即乙醇和相关化合物，包括一些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。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。

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.