Activity of Minimal NMDA Receptors

最小 NMDA 受体的活性

基本信息

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
项目类别：
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

项目摘要

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.

该项目将表征缺乏 N 端和 C 端的 NMDA 受体的功能特性结构域，本文称为最小受体。这些蛋白质构成了 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域 (ABD) 由跨膜（TMD）结构域组成。在父项目中，我们成功地使用了结构使用分子动力学构建这种最小受体的模型来设想 NMDA 受体的开放轨迹模拟。然而，目前尚不清楚最小受体是否具有功能，因此它们是否具有功能尚不清楚。基于以下生成的假设，代表进一步结构功能研究的合适模型我们的模拟。在此应用中，我们建议研究最小 NMDA 受体的假设显示谷氨酸介导的离子变性。我们的初步结果表明，最小的受体对谷氨酸通过产生与野生型受体动力学不同的兴奋性电流。通过描绘最小NMDA受体与天然NMDA受体激活机制的异同受体，该项目的结果将为正确解释结果提供必要的信息分子动力学模拟。