Gating Mechanism of NMDA Receptors

摘要 NMDA受体在中枢突触的正常发育和功能中起关键作用。突变体 最近在患有神经和精神疾病的患者中鉴定出受体， 与诊断出的功能障碍有关本项目的长期目标是将功能性受体与 由已建立的具有结构构象的动力学机制假设的状态。具体而言，两个目标 这里提出的将整合分子动力学模拟和电生理测量， 描绘了封闭和开放构象中成人NMDA受体亚型的合理构象， 一系列合理的目标和自然发生的病理性NMDA受体突变体。结果将 阐明NMDA受体门控反应和单残基取代改变的机制 结构和导致功能障碍。

Abstract NMDA receptors play critical roles during the normal development and function of central synapses. Mutant receptors were recently identified in patients with neurologic and psychiatric conditions and were found to be causal to the diagnosed dysfunctions. The long-term objective of this project is to correlate functional receptor states postulated by the established kinetic mechanism with structural conformations. Specifically, the two aims proposed here will integrate molecular dynamics simulations and electrophysiological measurements to delineate plausible conformations for the adult NMDA receptor isoform in closed and open conformations and for a series of rationally-targeted and naturally occurring, pathologic NMDA receptor mutants. Results will elucidate the NMDA receptor gating reaction and the mechanism by which single-residue substitutions change structure and cause dysfunction.