GLUTAMATE RECEPTOR COMPLEXES IN THE CENTRAL NERVOUS SYSTEM

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 在中枢神经系统中，神经元之间通过化学媒介的突触连接进行交流。突触前神经元释放的神经递质激活突触后神经元上的特定受体。哺乳动物中枢神经系统中的主要兴奋性神经递质是谷氨酸。突触细胞上的谷氨酸受体并不是孤立地出现在细胞表面，而是与广泛的蛋白质复合体相关。靠近突触后膜的蛋白质形成一个非常密集和有结构的组装，除了完整的膜蛋白外，还包括支架和适配器蛋白、激酶和磷酸酶。这种组装，通常被称为突触后密度(PSD)，是一个具有精致信号处理能力的专门细胞器。该复合体的正确功能对学习和记忆等高级大脑功能至关重要，人们认为许多人类疾病与该复合体的功能障碍有关，或由其功能障碍引起。该复合体的成分尚未完全确定，其信号机制也尚未完全了解。该项目将提供对其信号通路及其动态的更全面的表征。质谱学将用于识别翻译后修饰，如磷酸化，以及它们在从小鼠脑中分离的复合体的单个蛋白质中的准确位置。ITRAQ分析将被用来确定个别位点的磷酸化状态的动态。特别是，我们将分析来自遗传小鼠模型的改进的PSD准备，这些模型为更高的大脑功能提供信息，或者代表人类大脑疾病的真正模型。

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. In the central nervous system, neurons communicate with each other by chemically mediated synaptic connections. A neurotransmitter released by the presynaptic neuron activates specific receptors on the postsynaptic neuron. The main excitatory neurotransmitter in the mammalian central nervous system is glutamate. Glutamate receptors at synapses cell do not appear in isolation on the cell surface, but rather are associated with an extensive protein complex. Proteins close to the postsynaptic membrane form a very dense and structured assembly, which includes scaffolding and adaptor proteins, kinases and phosphatases in addition to integral membrane proteins. This assembly, often termed postsynaptic density (PSD), is a specialized organelle with exquisite signal processing capabilities. Its correct functioning is crucial for higher brain functions such as learning and memory, and it is thought that a number of human diseases are associated with, or caused by dysfunction of this complex.The components of this complex have not been completely determined, and its signaling mechanisms are only incompletely understood. This project will provide a more comprehensive characterization of its signaling pathways, and of their dynamics.Mass spectrometry will be used to identify posttranslational modifications, such as phosphorylation, and their precise location within individual proteins of the complex isolated from murine brains. iTRAQ analysis will be used to determine the dynamics of the phosphorylation state at individual sites. In particular we will analyze improved PSD preparations from genetic mouse models, which are informative for higher brain functions, or which represent genuine models of diseases of the human brain.