Permeation, Block, and Gating of NMDA Receptors

描述（由申请人提供）：本文提出的研究涉及N-甲基-D-天冬氨酸受体（NMDAR），这是一种由神经递质谷氨酸激活并介导神经元之间通信的脑蛋白。NMDAR是许多正常脑功能所必需的，例如记忆形成，并且还涉及许多人类疾病，包括阿尔茨海默病和精神分裂症。拟议研究的长期目标是深入了解NMDAR的功能，它们的外观以及与它们结合的药物如何改善或加剧神经系统疾病。将使用一种强有力的技术组合：记录脑切片内神经元和经修饰以表达特定类型NMDAR的细胞中NMDAR的电活动;使用分子生物学技术改变受体的化学组成并研究这些变化如何影响受体功能;记录单个受体的电活动;使用计算技术创建受体的物理组成模型，以提高对其结构的理解;使用其他计算技术创建受体的功能模型，以提高对其工作方式的理解。 提出了几个具体的研究目标。首先是研究NMDAR亚基之间如何相互作用。NMDAR由四个独立的子单位组成，它们以紧密集成的方式协同工作。一些亚基相互作用的区域已经被研究过了，但其他区域还没有。在拟议的研究中，将研究新发现的亚基相互作用区域的功能作用。第二个目标是根据相关蛋白质结构的知识和计算机模拟，开发一个更好的NMDAR结构模型。同时实现前两个目标将大大提高对NMDAR介导神经元通信的基本机制的理解。最终目标是了解与NMDAR结合的药物如何起作用。将被研究的一种药物用于治疗阿尔茨海默病，而另一种药物会导致正常人表现出精神分裂症的症状。这两种药物都能与NMDAR结合，但它们的作用截然不同。我们的目标是了解药物作用之间的重要差异，以深入了解药物特征，使一种药物能够帮助阿尔茨海默病患者，另一种药物能够模仿精神分裂症。

DESCRIPTION (provided by applicant): The research proposed here concerns N-methyl-D-aspartate receptors (NMDARs), brain proteins that are activated by the neurotransmitter glutamate and that mediate communication between neurons. NMDARs are required for many normal brain functions, such as memory formation, and also are involved in many human diseases, including Alzheimer's Disease and schizophrenia. The long-term objectives of the proposed research are to understand at a deep level how NMDARs function, what they look like, and how drugs that bind to them can either improve or exacerbate nervous system diseases. A powerful combination of techniques will be used: recording of the electrical activity of NMDARs in neurons within brain slices and from cells modified to express specific types of NMDARs; use of molecular biological techniques to change the chemical makeup of receptors and investigate how the changes affect receptor function; recording of the electrical activity of single receptors; use of computational techniques to create models of the physical makeup of receptors to improve understanding of their structure; use of other computational techniques to create functional models of receptors to improve understanding of how they work. Several specific research goals are proposed. The first is to investigate how NMDAR subunits interact with each other. NMDARs are composed of four separate subunits that work together in a tightly integrated manner. Some regions where subunits interact with each other have been studied, but others have not. In the proposed research, the functional role of a newly-discovered region where subunits interact will be studied. The second goal is to develop a better model of the structure of NMDARs based on knowledge of the structure of related proteins and on computer simulations. Accomplishing these first two goals together will greatly improve understanding of the basic mechanism by which NMDARs mediate neuronal communication. The final goal is to understand how drugs that bind to NMDARs work. One drug that will be studied is used to treat Alzheimer's disease, whereas the other drug causes normal humans to display the symptoms of schizophrenia. Both drugs bind to NMDARs, but they have very different effects. The goal is to understand the important differences between the actions of the drugs to provide insight into the drug characteristics that allow one to help Alzheimer's disease patients, and the other to mimic schizophrenia.