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Structure and mechanism of extrasynaptic GABAA receptors

突触外GABAA受体的结构和机制

基本信息

批准号：
10431870
负责人：
Dagimhiwat Legesse
金额：
$ 3.53万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10431870
关键词：
Acute Affinity Agonist Alcohols Analgesics Anesthesia procedures Anesthetics Anions Anticonvulsants Anxiety Barbiturates Benzodiazepines Bicuculline Binding Binding Sites Biochemical Biological Biological Assay Biophysics Brain Cerebellum Chlorides Chronic Cognition Complex Cryoelectron Microscopy Cytoplasmic Granules Data Data Set Disease Drug Receptors Drug abuse Electrophysiology (science)Emotions Epilepsy Ethanol Exhibits Extracellular Space Foundations Future GTP-Binding Protein alpha Subunits, Gs Goals Grant Intoxication Ion Channel Gating Ions Knockout Mice Lead Ligands Lipids Liposomes Mediating Membrane Modeling Molecular Conformation Motor Muscimol Neuraxis Neurons Neurotransmitter Receptor Neurotransmitters Pharmaceutical Preparations Pharmacology Physiological Play Point Mutation Postpartum Depression Preparation Process Property Proteins Recombinants Research Resolution Risk Role Sampling Scaffolding Protein Seizures Sensory Signal Transduction Site Sleep Specificity Structure Synapses Synaptic Receptors Testing Wakefulness Work addiction antagonist biophysical properties experimental study gamma-Aminobutyric Acid interest lipid I nanodisk nervous system disorder neurosteroids neurotransmission particle patch clamp radioligand receptor receptor binding receptor structure function reconstitution response sedative therapeutic target

项目摘要

Project Summary: Type A γ-aminobutyric acid receptors (GABAA) are pentameric ligand-gated ion channels found abundantly in the central nervous system. The binding of GABA, the major brain inhibitory neurotransmitter, to GABAA receptors, accounts for ~30% of the fast synaptic signaling in the brain. These receptors are important for sensory and motor processing, central autonomic control, and cognition. While much of the research in GABAA receptor structure and function has focused on the subunit assemblies found at synapses, a tremendous diversity of pharmacologically important GABAA receptor subtypes are found outside of synapses. The goal of this proposal is to determine and validate high-resolution structures of extrasynaptic GABAA receptors bound to distinct drug classes of relevance to neurological disorders, anesthesia, addiction and drug abuse. These receptors are potentiated by mildly intoxicating concentrations of ethanol, have high affinity for neurosteroids and are targets of anesthetics, analgesics, and anticonvulsant drugs. In two Aims, I propose to optimize conditions for expression and purification of defined heteromeric GABAA receptor assemblies, refine sample preparation for cryo-electron microscopy, collect and process single particle cryo-EM datasets, and build and refine atomic models of receptor-drug complexes. High-resolution structural information for physiologically important but understudied subunit assemblies, in complex with allosteric and orthosteric-site ligands will broadly inform on principles of ligand recognition and subunit assembly. !

项目概要： A型γ-氨基丁酸受体（GABAA）是一种五聚体配体门控离子通道，大量存在于中枢神经系统中GABA是主要的脑抑制性神经递质， GABAA受体占大脑中快速突触信号的约30%。这些受体很重要用于感觉和运动处理、中枢自主控制和认知。虽然大部分的研究在 GABAA受体的结构和功能集中在突触上发现的亚基组装上，这是一个巨大的挑战。在突触外发现了多种重要的GABAA受体亚型。的目标这项建议是确定和验证突触外GABAA受体的高分辨率结构，与神经系统疾病、麻醉、成瘾和药物滥用有关的不同药物类别。这些受体被轻度致醉浓度的乙醇增强，对神经类固醇具有高亲和力并且是麻醉剂、镇痛剂和抗惊厥药物的靶点。在两个目标中，我建议优化确定的异聚GABAA受体组装体的表达和纯化条件，精制样品冷冻电子显微镜的准备，收集和处理单粒子冷冻EM数据集，并建立和完善受体-药物复合物的原子模型。高分辨率的结构信息，重要但研究不足的亚基组装，与变构和正构位点配体复合，将广泛地告知配体识别和亚基组装的原理。 !