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: 9090149
• 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/9090149
• 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; Kainic Acid Receptors; Knowledge; Laboratories; Lipids; Mediating; Mental Retardation; Modeling; Molecular; Molecular Target; 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; 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.

 描述(由申请人提供)：NIH R01竞争性更新的这项提案的标题是“钙依赖蛋白激酶对谷氨酸受体的调节”。神经回路的失调会导致各种类型的神经疾病，包括癫痫、智力低下、自闭症和共济失调。神经回路是由神经元通过神经递质在突触上相互通信构成的。因此，控制突触传递对人类健康至关重要。谷氨酸是脑内一种主要的兴奋性神经递质，与三种离子亲性谷氨酸受体(AMPA、NMDA、海人酸型)结合。红藻氨酸受体定位于不同类型的突触，而AMPAR和NMDAR定位于大多数突触。AMPAR决定突触的强度，NMDAR通过激活钙依赖的激酶/磷酸酶来诱导突触的可塑性。神经元/NMDAR活性依赖于突触AMPAR活性的变化是大脑可塑性的关键机制。然而，蛋白激酶/磷酸酶的相关底物以及调节AMPAR活性的下游机制仍不清楚。在这里，我们旨在揭示通过调节AMPAR/TARP复合体来调节AMPAR活性的机制。我们已经研究了在突触稳定AMPAR的分子机制，并确定了TARP是AMPAR的一个辅助亚单位，以调节它们的通道特性和定位。我们将研究不同的TARP亚型在AMPAR定位、TARP磷酸化在基础传递和可塑性中的作用。控制突触传递是治疗突触传递中断引起的神经系统疾病的一种方法。了解控制突触传递和可塑性的分子机制有助于我们确定药物开发的分子靶点以损害神经功能障碍，而确定决定突触强度的关键分子是脑内兴奋性传递生物学中的一个关键问题。我们拟议的研究将提供与这个问题相关的基本知识。