The NMDA receptor 3B subunit in Motor Neuron Function

描述：(申请人提供) 谷氨酸的直接和间接毒性已被认为是一种主要的 导致运动神经元病的因素。谷氨酸毒性是通过以下途径介导的 N-甲基-D-天冬氨酸和丙二醛的离子型谷氨酸受体异常激活 非NMDA受体基因家族。我们最近克隆了一个新的成员 NMDAR家族，暂定为NR3B，表达 几乎只存在于运动神经元。值得注意的是，当在卵母细胞中共表达时 对于NR1和/或NR2A亚单位，NR3B显著改变了配体的特异性 以及NMDAR的离子渗透性以及它对通道的敏感性 拦截者。基于独特的电生理特性和表达 这个新的亚基的模式，我们假设NR3B亚基可能扮演一个 运动神经元功能的核心作用，例如，在维持 细胞内钙稳态，并可能解释观察到的差异 NMDAR在脊髓和脑中的药理作用。此外，我们建议一项 NR3B的正常表达、定位或加工中断 亚基可以促进运动神经元的特异性退化，例如 在肌萎缩侧索硬化症(ALS)和/或其他运动神经元中观察到的 疾病。将进行以下研究来检验这些假设： 具体目的1.NR3B亚单位表达改变NMDA的机制 我们将描述受体的功能。要做到这一点，分子轮廓和 脊髓运动神经元中NMDA受体的功能特性 将被描述为。特别是，我们将评估在多大程度上 NR3B表达水平和/或亚细胞定位的变化 发育和衰老影响NMDAR功能。 具体目标3.将产生NR3B基因缺失的小鼠品系并对其进行评估 运动神经元可能的病理变化。长期目标包括 NR3B相关运动神经元变性小鼠模型的建立 疾病。

DESCRIPTION: (provided by applicant) Glutamate toxicity, both direct and indirect, has been proposed to be a major factor contributing to motor neuron diseases. Glutamate toxicity is mediated by abnormal activation of ionotropic glutamate receptors of both the NMDA and non-NMDA receptor gene families. We have recently cloned a new member of the NMDA receptor (NMDAR) family, tentatively designated NR3B, which is expressed almost exclusively in motor neurons. Remarkably, when co-expressed in oocytes with NR1 and/or NR2A subunits, NR3B dramatically alters the ligand specificity and ion permeability of the NMDAR, as well as its sensitivity to channel blockers. Based on the unique electrophysiological properties and expression pattern of this new subunit, we hypothesize that the NR3B subunit may play a central role in motor neuron function, for example, in maintaining intracellular calcium homeostasis, and may explain the observed differences in NMDAR pharmacology in spinal cord versus brain. Furthermore, we propose that a disruption in the normal expression, localization, or processing of the NR3B subunit could contribute to specific degeneration of motor neurons, such as that observed in amyotrophic lateral sclerosis (ALS) and/or other motor neuron diseases. The following studies will be carried out to test these hypotheses: Specific Aim 1. The mechanism by which NR3B subunit expression alters NMDA receptor function will be delineated. To do this, the molecular profile and functional properties of NMDA receptors in motor neurons of the spinal cord will be characterized. In particular, we will evaluate the degree to which changes in NR3B expression level and/or subcellular localization during development and aging affect NMDAR function. Specific Aim 3. An NR3B-null mouse strain will be generated and evaluated for possible pathological changes in motor neurons. The long-term goals include the development of an NR3B-related mouse model for motor neuron degenerative diseases.