Regulation of glutamate receptors by calcium-dependent protein kinase

描述（由申请人提供）：本提案的总体目标是了解突触可塑性的机制，这可能是学习和记忆方面的基础，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储存信息，神经元活动会改变这些神经元回路中的突触强度。长期增强（Long-term potentiation， LTP）是大脑突触可塑性的一个成熟模型，即短暂的高频刺激会导致突触传递效率的突然和持续增加。脑内兴奋性突触以谷氨酸为主要神经递质，谷氨酸信号由2类嗜离子性谷氨酸受体介导，即nmda敏感的谷氨酸受体和ampa敏感的谷氨酸受体。在LTP期间，钙通过NMDA受体的内流通过蛋白激酶的激活增加突触上的功能性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尚不清楚。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）是关键分子。TARPs既调节AMPA受体到突触的运输，也调节突触通道的门控和药理学。TARPs在大脑中被定量磷酸化，LTP需要TARPs磷酸化；因此，TARPs是LTP的关键底物。我们现在建议确定TARPs的磷酸化如何调节AMPA受体运输，这可能是突触可塑性的基础。我们将确定TARPs中导致突触AMPA受体数量增加的激酶特异性磷酸化位点。我们还将确定以磷酸化依赖的方式与TARPs相互作用的分子。此外，我们将使用遗传方法来确定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。这些研究将为学习和记忆中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来治疗包括阿尔茨海默病、帕金森病等神经退行性疾病患者。公共卫生相关性：神经元回路在大脑中存储信息，这些神经元回路中的突触强度受神经元活动的影响。这项提议的总体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。这些研究将为学习和记忆中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来治疗包括阿尔茨海默病、帕金森病等神经退行性疾病患者。

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.