Regulation of glutamate receptors by calcium-dependent protein kinase

描述(由申请人提供)：这项建议的广泛目标是了解突触可塑性的机制，这些机制可能是学习和记忆的基础，特别是通过钙依赖蛋白磷酸化来调节谷氨酸受体。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到神经元活动的影响。长时程增强(LTP)是脑内已有的突触可塑性模型，即短暂的高频刺激可引起突触传递效率的突然而持续的增加。大脑中的兴奋性突触以谷氨酸为主要神经递质，谷氨酸信号由两类离子型谷氨酸受体、NMDA敏感型谷氨酸受体和AMPA敏感型谷氨酸受体介导。在LTP过程中，通过NMDA受体的钙内流通过激活蛋白激酶来增加突触上功能性的AMPA受体。然而，蛋白激酶/磷酸酶的相关靶点以及促进突触传递的下游机制仍不清楚。在过去的5年里，我研究了在突触稳定AMPA受体的分子机制，并确定跨膜AMPA受体调节蛋白(TARP)是关键分子。Tarp既调节AMPA受体向突触的运输，也调节突触处通道的门控和药理学。TARP在大脑中被定量地磷酸化，而LTP需要TARPS的磷酸化；因此，TARP是LTP中的关键底物。我们现在建议确定Tarp的磷酸化如何调节AMPA受体的运输，这可能是突触可塑性的基础。我们将确定在Tarp中导致突触AMPA受体数量增加的激酶特异性磷酸化位点。我们还将确定以依赖于磷酸化的方式与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。这些研究将为有关学习和记忆的兴奋性突触调节突触强度的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，用于治疗神经退行性疾病患者，包括阿尔茨海默病、帕金森病和其他疾病。与公共健康相关：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到神经元活动的影响。这一提议的广泛目标是了解突触可塑性的机制，这些机制可能是学习和记忆的基础。这些研究将为有关学习和记忆的兴奋性突触调节突触强度的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，用于治疗神经退行性疾病患者，包括阿尔茨海默病、帕金森病和其他疾病。

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.