STRUCTURAL STUDIES ON NEURORECEPTORS

神经感受器的结构研究

• 批准号: 8363338
• 负责人: Hiroyasu Furukawa
• 金额: $ 1.09万
• 依托单位: BROOKHAVEN SCIENCE ASSOC-BROOKHAVEN LAB
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8363338
• 关键词: Alzheimer' s Disease; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Binding; Biochemical; Biological; Cations; Cleaved cell; Crystallography; Electrophysiology (science); Enzymes; Funding; Glutamates; Glycine; Goals; Grant; Integral Membrane Protein; Ion Channel; LDL-Receptor Related Proteins; Ligands; Light; Lipoprotein Receptor; Mediating; Membrane; Molecular; N-Methyl-D-Aspartate Receptors; National Center for Research Resources; Neurons; Peptide Hydrolases; Play; Principal Investigator; Production; Property; Proteins; Proteolysis; Research; Research Infrastructure; Resources; Sensory Receptors; Site-Directed Mutagenesis; Source; Structure; Synaptic Transmission; Synchrotrons; Techniques; United States National Institutes of Health; base; cost; gamma secretase; neurotransmission; physical property; receptor; three dimensional structure

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The research in my group is aimed at understanding molecular basis for biological activity and physical properties of integral membrane receptors, enzymes and ion channels involved in neurotransmission. To achieve our goals, three-dimensional structures are determined primarily by x-ray crystallography and functional properties of target proteins are assessed by structure-based site-directed mutagenesis in combination with biophysical and biochemical techniques including electrophysiology. Specifically, we are focusing on three classes of integral membrane proteins, which play key roles in mediating neuronal activities: NMDA receptors, a ligand-gated cation channel that opens upon binding to glutamate and glycine and mediate excitatory synaptic transmission; LDL receptor related protein (LRP), a lipoprotein receptor that associate with NMDA receptors and regulate the strength of synaptic transmission; and gamma-secretase, an intramembrane cleaving protease (iCLIPs) that mediate regulated intramembrane proteolysis (RIP) of amyloid precursor protein (APP) to regulate the production of amyloid beta, a pathogenic product for Alzheimer's disease.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 我小组的研究旨在了解参与神经传递的完整膜受体、酶和离子通道的生物活性和物理特性的分子基础。为了实现我们的目标，三维结构主要通过 X 射线晶体学确定，并通过基于结构的定点诱变结合包括电生理学在内的生物物理和生化技术来评估目标蛋白的功能特性。 具体来说，我们关注三类整合膜蛋白，它们在介导神经元活动中发挥关键作用：NMDA受体，一种配体门控阳离子通道，在与谷氨酸和甘氨酸结合后打开并介导兴奋性突触传递； LDL受体相关蛋白（LRP），一种与NMDA受体结合并调节突触传递强度的脂蛋白受体； γ-分泌酶是一种膜内裂解蛋白酶 (iCLIP)，可介导淀粉样前体蛋白 (APP) 的调节性膜内蛋白水解 (RIP)，从而调节淀粉样蛋白 β 的产生，β 淀粉样蛋白是阿尔茨海默病的致病产物。