Structure and Function of GABA-A Receptors

GABA-A 受体的结构和功能

基本信息

批准号：
10307560
负责人：
Ryan E Hibbs
金额：
$ 49.78万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10307560
关键词：
Address Agonist Amino Acids Anesthetics Antibodies Anxiety Anxiety Disorders Architecture Barbiturates Behavior Benzodiazepines Binding Binding Sites Brain Cell Surface Receptors Chemicals Chemosensitization Chloride Channels Complement Complement 2 Complex Cryoelectron Microscopy Data Data Set Diazepam Disease Drug Targeting Electrophysiology (science)Environment Epilepsy Epitopes Equilibrium Ethanol Extracellular Domain Flumazenil Functional disorder GABA Agonists GABA-A Receptor GTP-Binding Protein alpha Subunits, Gs General anesthetic drugs Isoflurane Ligands Lipids Midazolam Modeling Molecular Monitor Mutagenesis Mutate Nervous System Physiology Nervous system structure Neuraxis Neurotransmitter Receptor Neurotransmitters Pentobarbital Pharmaceutical Preparations Pharmacology Physiological Preparation Propofol Protein Isoforms Proteins Publishing Recombinants Research Resolution Side Signal Transduction Site Sleeplessness Structure Sum Synapses Synaptic Membranes Therapeutic Transmembrane Domain Work antagonist drug mechanism drug of abuse excitotoxicity experimental study extracellular fascinate gamma-Aminobutyric Acid improved nanodisk neurosteroids neurotransmitter agonist positive allosteric modulator receptor reconstitution reconstruction therapeutic target

项目摘要

The GABA-A receptor is the most abundant inhibitory neurotransmitter receptor in the central nervous system and is the target of myriad therapeutic compounds and drugs of abuse. Function of the nervous system is governed by a balance of excitatory and inhibitory signaling; GABA-A receptor dysfunction results in disorders of anxiety and excitotoxicity including epilepsy. The principal isoform of this pentameric ligand-gated chloride channel is found on post-synaptic membranes in the brain. GABA (γ-aminobutyric acid) is the endogenous neurotransmitter and agonist of this receptor. Benzodiazepines, like diazepam (Valium) and midazolam (Versed), are positive allosteric modulators taken by 5% of the US for anxiety and insomnia. Barbiturates like pentobarbital, anesthetics like isoflurane and propofol, neurosteroids, and ethanol are all positive modulators acting through non-overlapping sites. This rich pharmacology derives from the complex subunit assembly of the synaptic GABA-A receptor. The predominant synaptic isoform consists of two α1 subunits, two β2 subunits and one γ2 subunit. Here we propose to address a lack of structural information on physiological GABA-A receptors using a direct approach. In three Specific Aims, we propose to elucidate the structural mechanism of benzodiazepine potentiation of these receptors, perform complementary electrophysiological experiments on the recombinant receptor, and in parallel characterize the structural principles underlying modulation by barbiturates, anesthetics and neurosteroids. The two structural Aims are independent and will yield fundamentally new and distinct structural information for the principal GABA-A receptor type in the central nervous system in complex with extracellular and transmembrane-site ligands. The functional Aim complements the structural work to define determinants for benzodiazepine binding, efficacy and allosteric signaling. The sum of structures and function will illuminate principles defining heteromer assembly and ligand recognition and will elucidate how drug binding changes molecular behavior, with broad relevance across the Cys-loop receptor superfamily.

GABA-A受体是中枢神经系统中最丰富的抑制性神经递质受体系统，是无数治疗化合物和滥用药物的目标。由兴奋性和抑制性信号传导的平衡控制；焦虑症和兴奋性毒性疾病，包括癫痫。这种五聚体配体门控的主要亚型。氯离子通道存在于大脑的突触后膜上。内源性神经递质和该受体的激动剂，如地西泮（安定）和咪达唑仑 (Versed) 是正变构调节剂，5% 的美国人服用它来治疗焦虑和失眠。戊巴比妥等巴比妥类药物、异氟烷和异丙酚等麻醉剂、神经类固醇和乙醇都是通过非重叠位点发挥作用的正调节剂这种丰富的药理学源自该复合物。突触 GABA-A 受体的亚基组装主要突触亚型由两个 α1 组成。亚基，两个β2亚基和一个γ2亚基在这里我们建议解决结构信息的缺乏。在三个具体目标中，我们建议阐明使用直接方法的生理学 GABA-A 受体。苯二氮卓类增强这些受体的结构机制，执行互补对重组受体进行电生理实验，并并行表征其结构巴比妥类药物、麻醉剂和神经类固醇调节的基本原理两个结构目标是。独立，将为主要 GABA-A 产生全新且独特的结构信息中枢神经系统中与细胞外和跨膜位点配体复合的受体类型。功能目标补充了结构工作，以确定苯二氮卓类药物结合、功效的决定因素结构和功能的总和将阐明定义异聚体的原理。组装和配体识别，并将阐明药物结合如何改变分子行为，具有广泛的意义 Cys 环受体超家族的相关性。