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: 8475617
• 负责人: Rongsheng Jin
• 金额: $ 28.68万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 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/8475617
• 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.

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，可形成跨膜阳离子渗透通道。iGluRs（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）中的快速兴奋性神经传递是必需的。AMPAR的功能障碍涉及几种神经退行性疾病，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，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，活性通道是仅通过相同亚家族内的亚基组装形成的四聚体，这是主要由胞外氨基末端结构域（ATD）控制的分子过程。这种现象用于控制iGluR离子通道的渗透和动力学性质，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引导亚家族特异性iGluR组装的分子机制。具体目标是：（1）我们将确定AMPAR的ATD的晶体结构;（2）我们将表征ATD在同聚和异聚AMPAR通道的功能组装中的作用;（3）我们将表征ATD引导iGluR的亚家族特异性二聚体-二聚体缔合的潜在机制。这项拟议的研究应该提供一个更好的理解的分子原则，管理iGluR的组装和功能，最终奠定了基础，为未来的治疗干预。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，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。