Regulation of glutamate receptors by calcium-dependent protein kinase

钙依赖性蛋白激酶对谷氨酸受体的调节

• 批准号: 7881729
• 负责人: Susumu Tomita
• 金额: $ 37.24万
• 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 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7881729
• 关键词: AMPA Receptors; Alzheimer' s Disease; Behavior; Biology; Brain; Calcium; Cells; Cognition; Communication; Cytoplasmic Tail; Development; Enhancers; Excitatory Synapse; Frequencies; Gated Ion Channel; Genetic; Glutamate Receptor; Glutamates; Goals; Hippocampus (Brain); In Vitro; Lead; Learning; Ligands; Long-Term Potentiation; Mass Spectrum Analysis; Mediating; Memory; Modeling; Molecular; Mus; Mutate; Mutation; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neurodegenerative Disorders; Neurons; Neurotransmitters; Parkinson Disease; Patients; Pattern; Peptide Mapping; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphorylation Site; Phosphotransferases; Play; Protein Family; Protein Isoforms; Protein Kinase; Proteins; Radio; Regulation; Role; Serine; Signal Transduction; Site; Synapses; Synaptic Transmission; Synaptic plasticity; Training; Transgenic Mice; calcium-dependent protein kinase; calmodulin-dependent protein kinase II; embryonic stem cell; genetic regulatory protein; granule cell; insight; interest; neurotransmission; postsynaptic; public health relevance; relating to nervous system; stargazin; trafficking

DESCRIPTION (provided by applicant): The broad goal of this proposal is to understand mechanisms for synaptic plasticity that may underlie aspects of learning and memory, especially for regulation of glutamate receptors by calcium-dependent protein phosphorylation. Neuronal circuits store information in the brain and the synaptic strength in these neuronal circuits is modified by neuronal activity. Long-term potentiation (LTP) is a well-established model for synaptic plasticity in the brain, that is, brief trains of high frequency stimulation cause an abrupt and sustained increase in the efficacy of synaptic transmission. Excitatory synapses in the brain use glutamate as the major neurotransmitter, and the glutamate signal is mediated by 2 classes of ionotropic glutamate receptors, NMDA-sensitive glutamate receptors and AMPA-sensitive glutamate receptors. During LTP, calcium influx through NMDA receptors increases functional AMPA receptors at synapses through the activation of protein kinases. However, the relevant targets for protein kinases/phosphatases and the downstream mechanisms that enhance synaptic transmission remain unclear. In the past 5 years I have studied the molecular machinery that stabilizes AMPA receptors at synapses and identified transmembrane AMPA receptor regulatory proteins (TARPs) as key molecules. TARPs modulate both trafficking of AMPA receptors to synapses and the gating and pharmacology of the channel at synapses. TARPs are quantitatively phosphorylated in the brain and LTP requires TARPs phosphorylation; thus, TARPs are critical substrates in LTP. We now propose to determine how phosphorylation of TARPs regulates the AMPA receptor trafficking that may underlie synaptic plasticity. We will determine the kinase-specific phosphorylation sites in TARPs that lead to increases in the number of synaptic AMPA receptors. We will also identify molecules that interact with TARPs in a phosphorylation-dependent manner. In addition, we will use genetic approaches to determine how targeted disruption of TARP phosphorylation modulates the synaptic targeting and stability of AMPA receptors. These studies will provide fundamental insights into the mechanisms that regulate synaptic strength at excitatory synapses regards to learning and memory. In addition, these studies will contribute to the development of pharmaceutical drugs as cognition enhancers to treat neurodegenerative disease patients including Alzheimer disease, Parkinson's disease and others. PUBLIC HEALTH RELEVANCE: Neuronal circuits store information in the brain and the synaptic strength in these neuronal circuits is modified by neuronal activity. The broad goal of this proposal is to understand mechanisms for synaptic plasticity that may underlie aspects of learning and memory. These studies will provide fundamental insights into the mechanisms that regulate synaptic strength at excitatory synapses regards to learning and memory. In addition, these studies will contribute to the development of pharmaceutical drugs as cognition enhancers to treat neurodegenerative disease patients including Alzheimer disease, Parkinson's disease and others.

描述（由申请人提供）：本提案的广泛目标是了解突触可塑性的机制，该机制可能是学习和记忆的基础，特别是通过钙依赖性蛋白磷酸化调节谷氨酸受体。神经元回路在大脑中存储信息，并且这些神经元回路中的突触强度被神经元活动修改。长时程增强（Long-term potentiation，LTP）是研究脑内突触可塑性的一种成熟模型，即短暂的高频刺激导致突触传递效率的突然和持续增加。大脑中的兴奋性突触使用谷氨酸作为主要的神经递质，并且谷氨酸信号由2类离子型谷氨酸受体介导，NMDA敏感性谷氨酸受体和AMPA敏感性谷氨酸受体。在LTP期间，通过NMDA受体的钙内流通过蛋白激酶的活化增加突触处的功能性AMPA受体。然而，蛋白激酶/磷酸酶的相关靶点和增强突触传递的下游机制仍不清楚。在过去的5年里，我研究了稳定突触AMPA受体的分子机制，并确定了跨膜AMPA受体调节蛋白（TARPs）作为关键分子。TARP调节AMPA受体向突触的运输以及突触处通道的门控和药理学。TARP在大脑中定量磷酸化，LTP需要TARP磷酸化;因此，TARP是LTP中的关键底物。我们现在建议确定如何磷酸化的TARP调节AMPA受体运输，可能是突触可塑性的基础。我们将确定导致突触AMPA受体数量增加的TARP中激酶特异性磷酸化位点。我们还将确定以磷酸化依赖方式与TARP相互作用的分子。此外，我们将使用遗传学方法来确定TARP磷酸化的靶向破坏如何调节AMPA受体的突触靶向和稳定性。这些研究将为了解兴奋性突触的突触强度调节机制提供基本的见解。此外，这些研究将有助于开发作为认知增强剂的药物，以治疗神经退行性疾病患者，包括阿尔茨海默病，帕金森病等。公共卫生相关性：神经元回路在大脑中存储信息，并且这些神经元回路中的突触强度被神经元活动修改。这项计划的主要目标是了解突触可塑性的机制，这可能是学习和记忆的基础。这些研究将为了解兴奋性突触的突触强度调节机制提供基本的见解。此外，这些研究将有助于开发作为认知增强剂的药物，以治疗神经退行性疾病患者，包括阿尔茨海默病，帕金森病等。