Structure/Function of the Extracellular Domain of iGluRs

描述（由申请人提供）：嗜离子性谷氨酸受体（iGluRs）是寡聚配体门控离子通道，负责介导大脑中的快速兴奋性神经传递。大的胞外结构域由氨基末端结构域（ATD）和配体结合结构域（S1S2）组成。本提案的总体目标是了解ATD在iGluRs的组装、激动剂/拮抗剂结合、通道门控和随后的脱敏中的作用。为了实现这一目标，提出了一种多方面的方法。一旦ATD或ATD- s1s2结构体被纯化，将检查其聚集状态和配体结合性质。随后对二聚体ATD或四聚体ATD- s1s2的结构分析得出的初步假设将通过位点定向诱变和完整受体中离子电导的电生理测量来验证。iGluR功能障碍与癫痫、中风和精神分裂症等疾病状态有关，因此，从本研究中获得的结构/功能关系的知识可能有助于开发新的治疗方法。

DESCRIPTION (provided by applicant): Ionotropic glutamate receptors (iGluRs) are oligomeric ligand-gated ion channels responsible for mediating fast excitatory neurotransmission in the brain. The large extracellular domain is composed of an amino terminal domain (ATD) and a ligand-binding domain (S1S2). The overall goal of this proposal is to understand the role of the ATD in assembly, agonist/antagonist binding, channel gating, and subsequent desensitization in iGluRs. To achieve this objective, a multifaceted approach is proposed. Once an ATD or ATD-S1S2 construct is purified, its aggregation state and ligand-binding properties will be examined. Initial hypotheses derived from subsequent structural analysis of either a dimeric ATD or tetrameric ATD-S1S2 will be tested by site-directed mutagenesis and electrophysiological measurements of ion conductance in the intact receptor. iGluR dysfunction has been implicated in disease states such as epilepsy, stroke, and schizophrenia and, thus, knowledge of the structure/function relationships obtained from this study may assist in the development of novel therapeutics.