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. 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.
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