Mechanisms of glycine receptor modulation by ethanol

乙醇调节甘氨酸受体的机制

• 批准号: 6691976
• 负责人: Michael Thomas Roberts
• 金额: $ 2.73万
• 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 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6691976
• 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（Glyrs）在介导对乙醇暴露的体内反应中起重要作用。尽管许多研究表征了乙醇对格素的直接作用，但Glyr功能的乙醇调节的分子机制仍然未知。我们建议使用斑块夹电生理学来研究乙醇对Glyr功能单通道特性的影响。 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.提出的实验将检验以下假设：乙醇和相关化合物（包括多种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。对酒精作用的分子机制的理解将有助于药物治疗酒精中毒的合理发展。