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

描述（由申请人提供）：嗜离子性谷氨酸受体（iGluRs）是配体门控离子通道，可形成跨膜、阳离子渗透通道。iGluRs （AMPA）亚型(S)-2-氨基-3-（3-羟基-5-甲基-4-异恶唑）丙酸（AMPA）对中枢神经系统（CNS）的快速兴奋性神经传递至关重要。AMPARs功能障碍与多种神经退行性疾病（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）有关。对于AMPARs以及其他iGluR亚家族，活性通道是由同一亚家族内亚基组装形成的四聚体，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，因此对维持iGluR的正常生理功能至关重要。本提案的目标是了解ATD引导亚家族特异性iGluR组装的分子机制。具体目的是：(1)确定AMPARs ATD的晶体结构；(2)我们将描述ATD在同质和异质AMPAR通道的功能组装中的作用；(3)我们将描述ATDs引导iGluRs亚家族特异性二聚体-二聚体关联的潜在机制。拟议的研究应该提供更好地理解控制iGluR组装和功能的分子原理，这可能最终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。

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.