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

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

展开

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，是无数治疗性化合物和滥用药物的靶标。神经系统的功能受兴奋和抑制信号的平衡控制； GABA-A受体功能障碍导致动画和兴奋性疾病，包括癫痫。该五聚体门控的主要同工型在大脑的突触后膜上发现了克利亚通道。 GABA（γ-氨基丁酸）是内源性神经递质和该受体的激动剂。苯二氮卓类，如地西ep（valium）和咪达唑仑（Versed）是美国5％的焦虑和失眠的阳性变构调节剂。巴比妥类药物，例如五核，麻醉药，例如异氟烷和建议，神经类固醇和乙醇，都是通过非重叠站点作用的正调节器。这种丰富的药理学源自该建筑群突触GABA-A受体的亚基组装。主要的合成同工型由两个α1组成亚基，两个β2亚基和一个γ2亚基。在这里，我们建议解决有关缺乏结构信息生理GABA-A受体使用直接方法。在三个特定目标中，我们建议阐明这些受体的苯二氮卓类药物的结构机制，执行完整性重组受体上的电生理实验，并并行表征结构巴比妥类药物，麻醉剂和神经类固醇的原理。两个结构的目的是独立并将为主要GABA-A产生新的新结构信息中枢神经系统中的受体类型与细胞外和跨膜点配体复合物。功能目标完成了结构性工作，以定义苯二氮卓的结合的确定词，有效性和变构信号。结构和功能的总和将阐明定义异构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，并以广泛的态度 CYS环受体超家族的相关性。