Molecular Physiology of NMDA Receptors

摘要 N-甲基-D-天冬氨酸(NMDA)受体活性产生富钙兴奋电流，控制 中枢突触的生理学。通过NMDA受体进行的兴奋性传递对 每时每刻的意识和认知。此外，渗透的钙会导致长期的变化。 突触启动学习和记忆形成的力量。过量NMDA受体介导的钙离子 进入会杀死神经元，是中风和与年龄相关的慢性病理的一种疾病机制，如 阿尔茨海默氏症和帕金森氏症。尽管对多种小分子调节剂敏感，但 作为治疗靶点的NMDA受体仍未实现，原因是对其结构的了解不足 使它们发生激活反应的变化。此外，基因测序在诊断方面的最新进展 已经在神经精神障碍患者中发现了大量独特的变种。其中许多 变异体是疾病的病因，但它们影响反应机制的机制，以及 因此功能是未知的。 这项研究计划的总体目标是描述NMDA受体的激活，包括 封闭、开放和不敏感状态之间的随机转换，具有结合原子- 从静态受体构象中获得粗粒度和原子性的水平结构信息 分子动力学模拟。这些结构结果将用动力学和热力学进行检验。 NMDA受体电流输出的测量。 在拟议的研究完成后，我们将确定每个具有代表性的原子结构 三种主要的功能状态(关闭、打开、不敏感)以及这些结构如何相互转换；将描绘 控制这些结构变化的关键原子相互作用；并将描述如何动态分布 这一构象地貌上的受体控制着去极化和钙内流的模式 由NMDA受体产生。此外，我们将询问由此产生的集成机制以 研究疾病相关突变和小分子调节剂如何影响构象动力学 受体以及它们如何改变NMDA受体电流。 该项目将生产一种可用于开发针对以下目标的小分子调制器的一致模型 特定的受体构象将独立于兴奋作用而减少钙流动，并将引导 NMDA受体基因变异患者的治疗方法。

Abstract N-methyl-D-aspartate (NMDA) receptor activity produces calcium-rich excitatory currents that control the physiology of central synapses. Ongoing excitatory transmission through NMDA receptors is essential for moment by moment consciousness and cognition. In addition, permeating calcium drives long-term changes in the strength of synapses to initiate learning and memory formation. Excessive NMDA receptor-mediated calcium entry kills neurons and is a disease mechanism in stroke and age-related chronic pathologies such as Alzheimer’s and Parkinson’s. Despite being sensitive to multiple small-molecule modulators, the potential of NMDA receptors as therapeutic targets remains unrealized due to insufficient knowledge about the structural changes that make their activation reaction. Moreover, recent advances in diagnosis with genetic sequencing has identified a large number of unique variants in patients with neuropsychiatric disorders. Many of these variants are causal to the disease, but the mechanism by which they affect the reaction mechanism, and therefore function is unknown. The overall objective of this research program is to describe the NMDA receptor activation, which consists of stochastic transitions between closed, open, and desensitized states, with a level of detail that integrates atomic- level structural information obtained from static receptor conformations with coarse-grained and atomistic molecular dynamic simulations. These structural results will be tested with kinetic and thermodynamic measurements of NMDA receptor current output. At the completion of the proposed study, we will have identified atomic structures representative for each of the three main functional states (closed, open, desensitized) and how these structures interconvert; will delineate key atomic interactions that control these changes in structure; and will describe how the dynamic distribution of receptors across this conformational landscape controls the patterns of depolarization and calcium influx produced by NMDA receptors. Furthermore, we will then interrogate the resulting integrated mechanism to examine how disease-related mutations and small-molecule modulators affect the conformational dynamics of receptors and how they alter the NMDA receptor current. The project will produce a congruent model that can be used to develop small-molecule modulators targeted to specific receptor conformations that would reduce calcium flux independently of excitatory action, and will guide therapeutic approaches for patients with dysfunctional NMDA receptor genetic variants.