Benzodiazepine Modulation of GABAa Receptor Kinetics

苯二氮卓类药物对 GABAa 受体动力学的调节

• 批准号: 6772441
• 负责人: CYNTHIA M CZAJKOWSKI
• 金额: $ 25.46万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-15 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6772441
• 关键词: GABA aminotransferase; GABA receptor; benzodiazepines; binding sites; cell line; central nervous system; chloride ion; gene mutation; membrane channels; neurotransmitter receptor; neurotransmitters; pharmacokinetics; radiotracer; receptor expression; voltage /patch clamp

DESCRIPTION (provided by applicant): Benzodiazepines (BDZs) exert anxiolytic and anti-epileptic effects in the central nervous system (CNS) by allosteric modulation of the GABAA receptor Cl- current (IGABA). Because of the widespread clinical utility of these drugs, understanding the mechanism(s) by which BDZs alter ion channel function is an important pharmacological inquiry. To identify the structural determinants underlying BDZ modulation of kinetic transitions of channel activation, one must first determine the effects of BDZs on identified, wild-type GABAA receptors. This will be approached using rapid drug application techniques and single-channel recordings to test which of the microscopic kinetic rate constants are altered by modulatory BDZs in a1 B2g2 receptors. We will make use of mutations in the GABA binding site, the pore region, and the extracellular loop to tease apart the contributions of BDZs to binding/unbinding and gating/desensitization of IGABA. We will also make use of tethered tandem subunits to functionally separate the contributions of each of the two GABA binding sites to these processes. The studies outlined in this application will help to establish the functional mechanisms of action for clinically relevant drugs on a major CNS variant of the GABAA receptor, and aid in establishing testable hypotheses regarding structure-function relationships in this and other ligand-gated ion channels.

描述（由申请人提供）：苯二氮卓类药物（BDZ）施加抗焦虑药 和抗癫痫作用在中枢神经系统（CNS）中通过变构作用 GABAA受体CL-电流（IGABA）的调节。因为广泛 这些药物的临床实用性，了解BDZ的机制 改变离子通道功能是重要的药理询问。识别 BDZ调制的结构决定因素的动力学转变 通道激活，必须首先确定BDZ对已识别的影响， 野生型GABAA受体。这将使用快速药物应用 技术和单渠道记录以测试哪些微观 动力学速率常数通过A1 B2G2受体中的调节性BDZ改变。我们 将利用GABA结合位点，孔区和 细胞外循环嘲笑BDZ的贡献 IGABA的结合/解开和门控/脱敏。我们还将利用 系绳串联亚基在功能上分开每个的贡献 两个GABA结合位点与这些过程。其中概述了 应用将有助于建立行动的功能机制 GABAA受体的主要中枢神经系统变体与临床相关的药物，并有助于 在建立有关结构功能关系的可检验假设 在此和其他配体门控离子通道中。