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

说明(申请人提供)：离子型谷氨酸受体(IGluRs)是配体门控离子通道，形成跨膜、阳离子通透通道。(S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazole)丙酸(AMPA)受体亚型是中枢神经系统快速兴奋性神经传递所必需的。AMPAR的功能障碍与阿尔茨海默病(AD)和肌萎缩侧索硬化症(ALS)等多种神经退行性疾病以及认知障碍、癫痫、精神分裂症和情绪障碍等其他神经系统疾病有关。对于AMPAR和其他iGluR亚家族，活性通道是由同一亚家族内的亚基组装而成的四聚体，这一分子过程主要由胞外氨基末端结构域(ATD)控制。这种现象控制着iGluR离子通道的通透性和动力学性质，因此对维持iGluR的正常生理功能至关重要。这项建议的目的是了解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在同质和异质AMPAR通道功能组装中的作用；以及(3)我们将表征ATD引导iGluRs亚家族特异性二聚体-二聚体结合的潜在机制。这项拟议的研究应该能更好地理解控制iGluR组装和功能的分子原理，最终可能为未来的治疗干预奠定基础。此外，控制iGluR组装的分子机制也可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、烟碱型乙酰胆碱受体、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。 公共卫生相关性：AMPA亚型谷氨酸受体(AMPAR)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的正常生理功能是由不同亚基之间的亚家族特异性通道组装主动控制的，它控制着离子通道的渗透和动力学特性。我们提出的研究应该能更好地理解控制iGluR组装的分子原理，这最终可能为未来的治疗干预奠定基础。

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.