Regulation of glutamate receptors by calcium-dependent protein kinases

钙依赖性蛋白激酶对谷氨酸受体的调节

• 批准号: 9266508
• 负责人: Susumu Tomita
• 金额: $ 41.63万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9266508
• 关键词: AMPA Receptors; Ataxia; Autistic Disorder; Binding; Biology; Brain; Calcium; Cerebellum; Complex; Epilepsy; Event; Excitatory Synapse; Glutamate Receptor; Glutamates; Goals; Health; Hippocampus (Brain); Human; Impairment; Kainic Acid Receptors; Knowledge; Laboratories; Lipids; Mediating; Mental Retardation; Modeling; Molecular; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neurobiology; Neurons; Neurotransmitters; Pattern; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Property; Protein Isoforms; Protein Kinase; Proteins; Regulation; Role; Synapses; Synaptic Transmission; Synaptic plasticity; United States National Institutes of Health; calcium-dependent protein kinase; calmodulin-dependent protein kinase II; drug development; genetic regulatory protein; kainate; molecular drug target; nervous system disorder; neural circuit; protein complex; public health relevance; stargazin; transmission process

 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.