SITES OF ACTION OF ALCOHOL ON GLYCINE RECEPTORS

酒精对甘氨酸受体的作用位点

• 批准号: 2769204
• 负责人: NEIL L. HARRISON
• 金额: $ 6.22万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-01 至 1999-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2769204
• 关键词: GABA receptor; Xenopus oocyte; animal genetic material tag; central nervous system; chimeric proteins; developmental genetics; ethanol; gamma aminobutyrate; glycine; glycine receptors; laboratory rat; neurogenetics; neurons; neuropharmacology; protein structure function; receptor binding; receptor expression; recombinant proteins; tissue /cell culture

DESCRIPTION: Central nervous system (CNS) depression caused by ethanol is a complex phenomenon which may involve several neurotransmitter systems. The present study aims to probe in detail the molecular mechanisms by which ethanol perturbs glycine receptor function. A strong case can now be made for the involvement of glycine and gamma-aminobutyric acid (GABA) in the CNS depressant actions of ethanol; enhancement of the actions of these inhibitory transmitters is consistent with the sedative and anesthetic effects of ethanol. The glycine and GABA receptors are related members of the 'superfamily' of ligand-gated ion channels. Homomeric glycine alpha1 or alpha2 receptors, like native glycine receptors, are quite sensitive to modulation by ethanol; the actions of glycine are potentiated by ethanol. The homomeric GABA receptor formed by the beta1 subunit is strongly inhibited by ethanol. This proposal aims to study the molecular mechanism of glycine receptor modulation by ethanol, by using a series of chimeric receptors by exchange of large or small domains of the human glycine receptor alpha2 and human GABA receptor gamma1 subunits. The hypotheses to be tested are: 1) that the human glycine receptor cc subunit possesses specific structural features which permit enhancement of agonist action by ethanol, and 2) that specific amino acid residues can be identified in the glycine receptor .2 subunit that are permissive for ethanol modulation. It is important to investigate the mechanisms of action of ethanol in order to have knowledge of the molecular mechanisms of this most widely abused drug.

描述：乙醇引起的中枢神经系统 (CNS) 抑制是一种 可能涉及多个神经递质系统的复杂现象。 这 本研究旨在详细探讨其分子机制 乙醇会扰乱甘氨酸受体功能。 现在可以提出强有力的理由 甘氨酸和γ-氨基丁酸（GABA）参与中枢神经系统 乙醇的抑制作用；加强这些行动 抑制性递质与镇静、麻醉药一致 乙醇的影响。 甘氨酸和 GABA 受体是相关成员 配体门控离子通道的“超家族”。 同聚甘氨酸α1或 α2 受体与天然甘氨酸受体一样，对 通过乙醇调节；乙醇可增强甘氨酸的作用。 由β1亚基形成的同聚GABA受体具有很强的 被乙醇抑制。 该提案旨在研究分子机制 通过使用一系列嵌合体，研究乙醇对甘氨酸受体的调节 通过交换人类甘氨酸的大或小结构域来形成受体 受体α2和人类GABA受体γ1亚基。 假设 被测试的是：1)人类甘氨酸受体cc亚基具有 允许增强激动剂作用的特定结构特征 乙醇，2) 可以在其中鉴定特定的氨基酸残基 允许乙醇调节的甘氨酸受体.2 亚基。 它 研究乙醇的作用机制非常重要 了解这种最广泛滥用的药物的分子机制。