The NMDA receptor 3B subunit in Motor Neuron Function

描述：（申请人提供） 谷氨酸毒性，直接和间接的，已被提出是一个主要的 导致运动神经元疾病的因素谷氨酸盐毒性是由 异常激活离子型谷氨酸受体的NMDA和 非NMDA受体基因家族。我们最近克隆了一个新成员， NMDA受体（NMDAR）家族，暂命名为NR 3B，在 几乎只存在于运动神经元中。值得注意的是，当在卵母细胞中共表达时 与NR 1和/或NR 2A亚基一起，NR 3B显著改变配体特异性 NMDAR的离子渗透性以及其对通道的敏感性 阻滞剂。基于独特的电生理特性和表达 这种新的亚基的模式，我们假设NR 3B亚基可能发挥作用， 在运动神经元功能中的中心作用，例如， 细胞内钙稳态，并可能解释观察到的差异， 脊髓与脑中的NMDAR药理学。此外，我们建议， NR 3B的正常表达、定位或加工的破坏 亚基可能有助于运动神经元的特异性变性，例如 在肌萎缩性侧索硬化症（ALS）和/或其它运动神经元中观察到 疾病将开展以下研究来检验这些假设： 具体目标1。NR 3B亚基表达改变NMDA的机制 将描述受体功能。为了做到这一点， 脊髓运动神经元NMDA受体的功能特性 将被定性。特别是，我们将评估 NR 3B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。将生成NR 3B-无效小鼠品系，并评价其 运动神经元可能的病理变化长期目标包括： NR 3B相关运动神经元退行性变小鼠模型的建立 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.