Regulation of glutamate receptors by calcium-dependent protein kinase

描述（由申请人提供）：该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质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由神经元活动改变。长时程增强（LTP）是大脑中突触可塑性的成熟模型，即短暂的高频刺激序列会导致突触传递效率突然而持续的增加。大脑中的兴奋性突触使用谷氨酸作为主要的神经递质，谷氨酸信号由两类离子型谷氨酸受体介导，即NMDA敏感谷氨酸受体和AMPA敏感谷氨酸受体。在 LTP 期间，钙离子通过 NMDA 受体流入，通过激活蛋白激酶，增加突触处 AMPA 受体的功能。然而，蛋白激酶/磷酸酶的相关靶点以及增强突触传递的下游机制仍不清楚。在过去的 5 年里，我研究了稳定突触处 AMPA 受体的分子机制，并确定了跨膜 AMPA 受体调节蛋白 (TARP) 作为关键分子。 TARP 调节 AMPA 受体向突触的运输以及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，TARP 是 LTP 中的关键底物。我们现在建议确定 TARP 的磷酸化如何调节可能构成突触可塑性的 AMPA 受体运输。我们将确定 TARP 中导致突触 AMPA 受体数量增加的激酶特异性磷酸化位点。我们还将鉴定以磷酸化依赖性方式与 TARP 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。这些研究将为调节学习和记忆兴奋性突触突触强度的机制提供基本见解。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。公共健康相关性：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会受到神经元活动的影响。该提案的总体目标是了解可能构成学习和记忆方面基础的突触可塑性机制。这些研究将为调节学习和记忆兴奋性突触突触强度的机制提供基本见解。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。

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.