Regulation of glutamate receptors by calcium-dependent protein kinases

 描述（由申请人提供）：NIH R 01竞争性更新的提案标题为“钙依赖性蛋白激酶对谷氨酸受体的调节”。神经回路的失调导致各种类型的神经系统疾病，包括癫痫、精神发育迟滞、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处相互通信构成的。因此，控制突触传递对人类健康至关重要。谷氨酸是大脑中主要的兴奋性神经递质，并结合三种离子型谷氨酸受体（AMPA、NMDA、红藻氨酸型）。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决定突触强度，NMDAR通过激活钙依赖性激酶/磷酸酶诱导突触可塑性。突触AMPAR活性的神经元/NMDAR活性依赖性变化代表了脑可塑性的关键机制。然而，蛋白激酶/磷酸酶的相关底物和调节AMPAR活性的下游机制仍不清楚。在这里，我们的目的是揭示通过AMPAR/TARP复合物的调制AMPAR活性的机制。我们已经研究了在突触处稳定AMPAR的分子机制，并将TARP鉴定为AMPAR的辅助亚基，以调节其通道特性和定位。我们将研究不同的TARP亚型在AMPAR定位，TARP磷酸化在基础传输和可塑性的作用。控制突触传递是治疗由突触传递中断引起的神经障碍的一种方法。了解控制突触传递和可塑性的分子机制使我们能够确定用于药物开发的分子靶标以损害神经系统疾病，并且确定决定突触强度的关键分子是大脑兴奋性传递生物学中的关键问题。我们提出的研究将提供与这个问题有关的基本知识。

 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.