Activity of Minimal NMDA Receptors

最小 NMDA 受体的活性

• 批准号: 10743773
• 负责人: Gabriela K Popescu
• 金额: $ 3.74万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10743773
• 关键词: Address; Agonist; Architecture; Binding; C-terminal; Central Nervous System; Characteristics; Computer Models; Computer Simulation; Coupled; Cryoelectron Microscopy; Data; Development; Disease; Electrophysiology (science); Family; Functional disorder; Glutamate Receptor; Glutamates; Goals; Grain; Hot Spot; Image; Intervention; Investigation; Ion Channel; Ions; Kinetics; Knowledge; Length; Link; Maps; Measurement; Mediating; Missense Mutation; Modeling; Molecular Conformation; Movement; Mutation; N-Methyl-D-Aspartate Receptors; N-terminal; Neurotransmitter Receptor; Output; Pathology; Patients; Permeability; Property; Protein Isoforms; Proteins; Reaction; Receptor Activation; Receptor Gene; Records; Rest; Roentgen Rays; Role; Series; Shapes; Site; Specificity; Structural Models; Structure; Synaptic Transmission; Synaptic plasticity; Testing; Thermodynamics; Transmembrane Domain; antagonist; clinically relevant; computerized tools; desensitization; disease-causing mutation; extracellular; kinetic model; member; molecular dynamics; molecular modeling; mutant; neurophysiology; neuropsychiatric disorder; parent grant; parent project; pharmacologic; prevent; protein structure; receptor; simulation

This project will characterize the functional properties of NMDA receptors that lack N-terminal and C-terminal domains, herein referred to as minimal receptors. These proteins consist of the core machinery of NMDA receptors and include the extracellular agonist-binding domain (ABD) connected to the ion-permeable pore formed by the transmembrane (TMD) domain. In the parent project, we were successful in using a structural model of this minimal receptor to envision the opening trajectory of NMDA receptors, using molecular dynamics simulations. However, it is unknown whether the minimal receptors are functional and therefore whether they represent a suitable model for further structure-function investigations, based on the hypotheses generated by our simulations. In this application, we propose to investigate the hypothesis that minimal NMDA receptors display glutamate-mediated ionotropy. Our preliminary results demonstrate that minimal receptors respond to glutamate by producing excitatory currents that differ in kinetics from wild-type receptors. By delineating commonalities and differences between the activation mechanism of minimal NMDA receptors and native receptors, results from this project will provide information necessary for the correct interpretation of results from molecular dynamics simulations.

本计画将探讨缺乏N端及C端之NMDA受体之功能特性 结构域，本文称为最小受体。这些蛋白质组成了NMDA的核心机制 受体，并包括连接到离子渗透孔的细胞外激动剂结合结构域（ABD 由跨膜（TMD）结构域形成。在母项目中，我们成功地使用了一种结构 这个最小受体的模型，设想开放的NMDA受体的轨迹，使用分子动力学 模拟然而，目前尚不清楚最小受体是否有功能，因此它们是否 代表了一个合适的模型，进一步的结构功能研究，根据所产生的假设 我们的模拟。在本申请中，我们建议调查的假设，最小的NMDA受体 显示谷氨酸介导的离子迁移性。我们的初步结果表明，最小的受体反应， 通过产生动力学上不同于野生型受体的兴奋性电流来调节谷氨酸。通过划定 最小NMDA受体和天然NMDA受体的激活机制之间的共性和差异 受体，本项目的结果将提供正确解释结果所需的信息， 分子动力学模拟