The amino-terminal domain guides subfamily-specific assembly of ionotropic glutam

氨基末端结构域指导离子型谷氨酸的亚家族特异性组装

• 批准号: 8070499
• 负责人: Rongsheng Jin
• 金额: $ 36.87万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8070499
• 关键词: Address; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Biochemical; Brain; Cations; Cells; Cellular biology; Cholinergic Receptors; Cognitive deficits; Crystallization; Dimerization; Electrophysiology (science); Elements; Ensure; Epilepsy; Extracellular Domain; Future; GABA Receptor; Gated Ion Channel; Gatekeeping; GluR2 subunit AMPA receptor; Glutamate Receptor; Goals; Hand; Homodimerization; Human; Insecta; Ion Channel; Isoxazoles; Kainic Acid Receptors; Kinetics; Knowledge; Learning; Length; Ligand Binding Domain; Ligands; Link; Long-Term Potentiation; Manuals; Mediating; Memory; Mental disorders; Methods; Modeling; Molecular; Mood Disorders; National Institute of Child Health and Human Development; Nature; Neuraxis; Neurodegenerative Disorders; Nicotinic Receptors; Physiological; Potassium Channel; Process; Property; Propionic Acids; Protein Engineering; Recombinants; Regulation; Resolution; Role; Schizophrenia; Sequence Analysis; Site-Directed Mutagenesis; Structure; Surface; Synaptic plasticity; Testing; Therapeutic Intervention; Ultracentrifugation; Voltage-Gated Potassium Channel; Work; Xenopus oocyte; base; cyclic-nucleotide gated ion channels; desensitization; dimer; extracellular; high throughput screening; insight; kainate; mutant; nervous system disorder; neurotransmission; polypeptide; prevent; public health relevance; receptor; receptor function; research study; stoichiometry; structural biology

DESCRIPTION (provided by applicant): Ionotropic glutamate receptors (iGluRs) are ligand-gated ion channels that form transmembrane, cation- permeable channels. The (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazole) propionic acid (AMPA) subtype of iGluRs (AMPAR) is essential for the fast excitatory neurotransmission in the central nervous system (CNS). Malfunction of AMPARs has been implicated in several neurodegenerative diseases such as Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS), as well as other neurological diseases such as cognitive deficits, epilepsy, schizophrenia, and mood disorders. For AMPARs as well as other iGluR subfamilies, active channels are tetramers exclusively formed by assembly of subunits within the same subfamily, a molecular process principally controlled by the extracellular amino-terminal domain (ATD). This phenomenon serves to control the permeation and kinetic properties of iGluR ion channels and is thus critical for maintaining normal physiological function of iGluRs. The goals of this proposal are to understand the molecular mechanisms by which the ATD guides subfamily-specific iGluR assembly. The specific aims are: (1) we will determine the crystal structures of the ATD of AMPARs; (2) we will characterize the role of the ATD in functional assembly of homomeric and heteromeric AMPAR channels; and (3) we will characterize the underlying mechanism by which ATDs guide subfamily-specific dimer-dimer association of iGluRs. The proposed study should provide a better understanding of the molecular principles governing iGluR assembly and function which could ultimately lay groundwork for future therapeutic interventions. Furthermore, molecular mechanisms governing iGluR assembly could be applicable for studying other multimeric ion channels/receptors, such as potassium channels, cyclic nucleotide-gated channels, nicotinic acetylcholine receptors, GABA receptors and others. Aberrant structure or function of these receptors/channels has been linked to many human neurological and psychiatric diseases. PUBLIC HEALTH RELEVANCE: Malfunction of the AMPA subtype glutamate receptors (AMPARs) has been implicated in neurodegenerative diseases such as Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS), as well as other neurological diseases. The normal physiological functions of AMPARs are actively controlled by subfamily-specific channel assembly between different subunits which serves to control the permeation and kinetic properties of ion channels. Our proposed study should provide a better understanding of the molecular principles governing iGluR assembly, which could ultimately lay groundwork for future therapeutic interventions.

描述（由申请人提供）：离子型谷氨酸受体（iGluR）是配体门控离子通道，形成跨膜、阳离子可渗透通道。 iGluR (AMPAR) 的 (S)-2-氨基-3-(3-羟基-5-甲基-4-异恶唑)丙酸 (AMPA) 亚型对于中枢神经系统 (CNS) 的快速兴奋性神经传递至关重要。 AMPAR 的功能障碍与多种神经退行性疾病有关，例如阿尔茨海默病 (AD) 和肌萎缩侧索硬化症 (ALS)，以及其他神经系统疾病，例如认知缺陷、癫痫、精神分裂症和情绪障碍。对于 AMPAR 以及其他 iGluR 亚家族，活性通道是由同一亚家族内的亚基组装专门形成的四聚体，这一分子过程主要由细胞外氨基末端结构域 (ATD) 控制。这种现象有助于控制 iGluR 离子通道的渗透和动力学特性，因此对于维持 iGluR 的正常生理功能至关重要。该提案的目标是了解 ATD 指导亚家族特异性 iGluR 组装的分子机制。具体目标是：（1）确定AMPARs ATD的晶体结构； (2) 我们将描述 ATD 在同聚和异聚 AMPAR 通道功能组装中的作用； (3)我们将描述ATD引导iGluR亚家族特异性二聚体-二聚体关联的潜在机制。拟议的研究应该可以更好地理解控制 iGluR 组装和功能的分子原理，这最终可以为未来的治疗干预奠定基础。此外，控制 iGluR 组装的分子机制可适用于研究其他多聚体离子通道/受体，例如钾通道、环核苷酸门控通道、烟碱乙酰胆碱受体、GABA 受体等。这些受体/通道的异常结构或功能与许多人类神经和精神疾病有关。 公共健康相关性：AMPA 亚型谷氨酸受体 (AMPAR) 的功能障碍与阿尔茨海默病 (AD) 和肌萎缩侧索硬化症 (ALS) 等神经退行性疾病以及其他神经系统疾病有关。 AMPAR 的正常生理功能由不同亚基之间的亚家族特异性通道组装主动控制，该通道组装用于控制离子通道的渗透和动力学特性。我们提出的研究应该可以更好地理解控制 iGluR 组装的分子原理，这最终可以为未来的治疗干预奠定基础。