STRUCTURAL STUDIES ON NEURORECEPTORS

神经感受器的结构研究

• 批准号: 8170676
• 负责人: Hiroyasu Furukawa
• 金额: $ 1.73万
• 依托单位: BROOKHAVEN SCIENCE ASSOC-BROOKHAVEN LAB
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8170676
• 关键词: Alzheimer' s Disease; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Binding; Biochemical; Biological; Cations; Cleaved cell; Computer Retrieval of Information on Scientific Projects Database; Crystallography; Electrophysiology (science); Enzymes; Funding; Glutamates; Glycine; Goals; Grant; Institution; Integral Membrane Protein; Ion Channel; LDL-Receptor Related Proteins; Ligands; Lipoprotein Receptor; Mediating; Membrane; Molecular; N-Methyl-D-Aspartate Receptors; Neurons; Peptide Hydrolases; Play; Production; Property; Proteins; Proteolysis; Research; Research Personnel; Resources; Role; Sensory Receptors; Site-Directed Mutagenesis; Source; Structure; Synaptic Transmission; Techniques; United States National Institutes of Health; base; 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. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 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，一种膜内裂解蛋白酶 (iCLIP)，可介导淀粉样前体蛋白 (APP) 的调节膜内蛋白水解 (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。