Trafficking and Regulation of the NMDA Receptor Subunit NR2C

项目总结（见说明）： 我研究的长期目标是了解NMDA受体调节突触传递强度的分子机制，并利用这些信息开发治疗神经和精神疾病的治疗策略。NMDA受体向突触部位的有效运输对于正常的兴奋性神经传递是至关重要的。NMDA受体的胞内结构域与胞质蛋白结合，并作为蛋白激酶的底物，从而调节突触 表达和功能。NMDA受体由不同的亚基组成，在整个CNS中具有独特的表达，并具有特定的功能和特性。该提案涉及NMDA受体亚基NR2C在NMDA受体调节和贩运中的作用。NR2C赋予NMDA受体产生通道的独特性质，该通道对镁离子的电压依赖性阻断相对不敏感。NR2C在小脑、丘脑和嗅球中高度富集。因此， NR2C表面表达和功能可能是在这些脑区中定义NMDA受体特性的关键。本论文将结合分子生物学、生物化学和细胞生物学的方法来研究NR2C表面表达的调控和含有NR2C的NMDA受体的功能。目的：1）明确含NR2C的NMDA受体在神经元存活中的作用，并阐明其信号通路。2)定义NR2C磷酸化在NMDA受体调控和运输中的作用。3)明确小脑NMDA受体亚单位特异性调控的分子机制。 这些研究的成功完成，预计将提供第一个详细的检查NR2C的调节，并提供深入了解NR2C受体的小脑功能的功能意义。

PROJECT SUMMARY (See instructions): The long-term goal of my research is to understand the molecular mechanism by which NMDA receptors are regulated to modulate the strength of synaptic transmission, and to use this information for development of therapeutic strategies to treat neurological and psychiatric diseases. Efficient trafficking of NMDA receptors to synaptic sites is critical for normal excitatory neurotransmission. Intracellular domains of NMDA receptors bind to cytosolic proteins and serve as substrates for protein kinases, thereby regulating synaptic expression and function. NMDA receptors are made up of distinct subunits with unique expression throughout the CNS and with specific function and properties. This proposal addresses the role of the NMDA receptor subunit NR2C in NMDA receptor regulation and trafficking. NR2C confers unique properties on NMDA receptors producing channels relatively insensitive to the voltage-dependent block by magnesium ions. NR2C is highly enriched in cerebellum, thalamus and olfactory bulb. Thus the mechanisms regulating NR2C surface expression and function are likely to be critical in defining NMDA receptor properties in these brain regions. I will use a combination of molcular biology, biochemistry and cell biology to characterize the regulation of NR2C surface expression and the function of NR2C-containing NMDA receptors. The goals are to: 1) Define the role of NR2C-containing NMDA receptors in neuronal survival and elucidate its signaling pathway. 2) Define the role of NR2C phosphorylation in the regulation and trafficking of NMDA receptors. 3) Define the molecular mechanisms underlying subunit-specific regulation of NMDA receptors in cerebellum. The successful completion of these studies is expected to provide the first detailed examination of the regulation of NR2C and provide insight into the funcitonal significance of NR2C-containing receptors for cerebellar funciton.