Regulation of glutamate receptors by calcium-dependent protein kinase

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DESCRIPTION (provided by applicant): The title of this proposal for the NIH R01 competing renewal is "Regulation of glutamate receptors by calcium-dependent protein kinases". Dysregulation of neural circuits causes various types of neurological disorders including epilepsy, mental retardation, autism and ataxia. Neural circuits are constructed by neurons that communicate each other at synapses through neurotransmitters. Therefore, controlling synaptic transmission is crucial for human health. Glutamate is a major excitatory neurotransmitter in the brain and binds to three classes of ionotropic glutamate receptors (AMPA, NMDA, kainate-type). Whereas kainate receptors localize at distinct types of synapses, AMPARs and NMDARs localize at most synapses. AMPAR determines synaptic strength and NMDAR induces synaptic plasticity through activation of calcium dependent kinases/phosphatases. Neuronal/NMDAR activity- dependent changes in synaptic AMPAR activity represent a key mechanism for brain plasticity. However, the relevant substrates for protein kinases/phosphatases and the downstream mechanisms that regulate AMPAR activity remain unclear. Here, we aim to reveal mechanisms for modulating AMPAR activity through modulation of AMPAR/TARP complex. We have studied the molecular machinery that stabilizes AMPARs at synapses and identified TARPs as an auxiliary subunit of AMPARs to modulate their channel properties and localization. We will examine roles of distinct TARP isoform in AMPAR localization, TARP phosphorylation in basal transmission and plasticity. Controlling synaptic transmission is one approach to treat neurological disorders caused by disruption of synaptic transmission. Understanding molecular mechanisms to control synaptic transmission and plasticity allows us to identify molecular target for drug development to impair neurological disorders, and identification of critical molecules determining synaptic strength is a key issue in the biology of excitatory transmission in the brain. Our proposed studies will provide fundamental knowledge relevant to this question.