Conformational mechanisms of mGluR gating and regulation

mGluR 门控和调节的构象机制

• 批准号: 10665636
• 负责人: Ehud Isacoff
• 金额: $ 40.13万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10665636
• 关键词: Affinity; Allosteric Regulation; Arrestins; Biological Assay; Brain; Cells; Coupled; Diffusion; Dimerization; Drug Targeting; Enzymes; Fluorescence Resonance Energy Transfer; G-Protein-Coupled Receptors; GTP-Binding Proteins; Glutamates; Goals; Heterodimerization; Homo; Hybrids; Intercellular Junctions; Label; Ligands; Membrane; Metabotropic Glutamate Receptors; Methods; Modeling; Molecular; Molecular Conformation; Monitor; Nervous System; Neuroglia; Neurotransmitter Receptor; Neurotransmitters; Optical Methods; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Property; Proteins; Pump; Receptor Activation; Receptor Signaling; Regulation; Rotation; Signal Transduction; Signaling Protein; Site; Stimulus; Structure; Subgroup; Synapses; Synaptic Cleft; Synaptic Transmission; Tertiary Protein Structure; Testing; Work; design; dimer; drug development; extracellular; fascinate; member; nervous system disorder; neurotransmitter release; pharmacologic; positive allosteric modulator; postsynaptic; presynaptic; presynaptic neurons; receptor; receptor function; response; spatiotemporal; synaptic inhibition; transmission process

SUMMARY/ABSTRACT G-protein–coupled receptors (GPCRs), the largest class of membrane signaling proteins, respond to a wide array of extracellular stimuli to initiate intracellular signaling via G proteins and arrestins. Recent studies have provided snapshots of GPCR structures in distinct conformations and revealed that they are extremely dynamic. The conformational dynamics appear to be central to ligand recognition, activation and signaling. Membrane receptors have evolved to respond to precise spatio-temporal concentration profiles of extracellular ligands. In the nervous system, neurotransmitter receptors encounter a wide range of neurotransmitter concentrations and spatio-temporal profiles. Key factors are the small extracellular volume of the synaptic cleft, pumps and/or enzymes that remove neurotransmitter, and diffusion. Additionally, neurotransmitter receptors can be localized within the synapse both pre- and postsynaptically, as well as extrasynaptically where they can encounter neurotransmitter released either locally, which briefly reaches low millimolar levels within the cleft, and spillover from nearby synapses, which reaches lower concentrations. Metabotropic glutamate receptors (mGluRs) are found pre- and postsynaptically at excitatory glutamatergic synapses, as well as on glia and at inhibitory GABAergic presynaptic nerve terminals, meaning that they are activated by both high local concentrations near the site of release and spillover. mGluRs of various kinds can be found together in presynaptic nerve terminals, even when they are all coupled to the same G protein. And they can dimerize, generating hybrid or in some cases totally unique properties and pharmacological profiles. To understand what each mGluR subtype does and develop effective drugs to treat the neurological disorders in which they are implicated, we need to understand how they function and how they are regulated. Our goal here is to define the molecular mechanisms that set and regulate the functional properties of homo- and heteromeric mGluRs at synapses and put into place assays that can be used to screen modulation in the nervous system.

摘要/摘要 G 蛋白偶联受体 (GPCR) 是最大的一类膜信号蛋白，对广泛的信号反应 最近的研究表明，一系列细胞外刺激可通过 G 蛋白和抑制蛋白启动细胞内信号传导。 快照提供了不同构象的 GPCR 结构，并表明它们极其 构象动力学似乎是配体识别、激活和信号传导的核心。 膜受体已经进化到能够对细胞外的精确时空浓度曲线做出反应 在神经系统中，神经递质受体遇到多种神经递质。 浓度和时空分布的关键因素是突触间隙的细胞外体积小， 去除神经递质的泵和/或酶，以及神经递质受体的扩散。 可以定位在突触内，突触前和突触后，以及突触外 遇到局部释放的神经递质，该递质在裂隙内短暂达到低毫摩尔水平， 以及来自附近突触的溢出，其浓度较低。 (mGluR) 存在于兴奋性谷氨酸突触的突触前和突触后，以及神经胶质细胞和神经胶质细胞上。 抑制性 GABA 能突触前神经末梢，这意味着它们被局部高电位激活 释放和溢出部位附近的各种 mGluR 浓度可以一起在以下位置找到。 突触前神经末梢，即使它们都与相同的 G 蛋白偶联，并且它们可以二聚化， 产生混合或在某些情况下完全独特的特性和药理学特征以了解什么。 每个 mGluR 亚型都确实并正在开发有效的药物来治疗其所在的神经系统疾病 涉及其中，我们需要了解它们如何运作以及如何监管。我们的目标是定义它们。 设置和调节同聚和异聚 mGluR 功能特性的分子机制 突触并进行可用于筛选神经系统调节的测定。

项目成果

Conformational basis of subtype-specific allosteric control of NMDA receptor gating.

NMDA 受体门控亚型特异性变构控制的构象基础。

• DOI: 10.1101/2024.02.10.579740
• 发表时间: 2024
• 期刊: bioRxiv : the preprint server for biology
• 作者: Bleier,Julia;deMendonca,PhilipeRibeiroFurtado;Habrian,Chris;Stanley,Cherise;Vyklicky,Vojtech;Isacoff,EhudY
• 通讯作者: Isacoff,EhudY