Trafficking and Regulation of the NMDA Receptor Subunit NR2C

我研究的长期目标是了解NMDA受体 调节突触传递的强度，并将此信息用于发育 神经和精神疾病的治疗策略。高效贩运NMDA 突触部位的受体对于正常的兴奋性神经传递至关重要。NMDA胞内结构域 受体与胞质蛋白结合，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，具有独特的表达 在中枢神经系统中具有特定的功能和特性。这项建议涉及国家地雷行动局的作用， 受体亚基NR2C参与NMDA受体的调节和运输。NR2C赋予独特的性质， NMDA受体产生通道对镁离子的电压依赖性阻滞相对不敏感 离子。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在这些细胞中定义NMDA受体特性方面至关重要。 大脑区域。我将结合分子生物学、生物化学和细胞生物学来描述 NR2C表面表达的调节和含NR2C的NMDA受体的功能。这些目标是 目的：1）确定含NR2C的NMDA受体在神经元存活中的作用并阐明其信号传导 通路2)定义NR2C磷酸化在NMDA受体调控和运输中的作用。第三章 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，预计将首次详细审查 调节NR2C，并提供深入了解NR2C受体的功能意义， 小脑功能

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.