The NMDA receptor 3B subunit in Motor Neuron Function

NMDA 受体 3B 亚基在运动神经元功能中的作用

• 批准号: 6623376
• 负责人: DONGXIAN ZHANG
• 金额: $ 37.62万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6623376
• 关键词: NMDA receptors; cell line; gene expression; gene targeting; genetically modified animals; glutamate receptor; glutamates; immunocytochemistry; laboratory mouse; motor neurons; nervous system disorder; neural degeneration; neurotoxicology; neurotoxins; pathologic process; protein localization; protein structure function; receptor expression; spinal cord; tissue /cell culture; voltage /patch clamp

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.

描述：（由申请人提供） 谷氨酸毒性，无论是直接的还是间接的，已被认为是主要的毒性。 导致运动神经元疾病的因素。谷氨酸毒性是由 NMDA 和离子型谷氨酸受体的异常激活 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，暂定为 NR3B，其表达 几乎完全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 NR1 和/或 NR2A 亚基一起，NR3B 显着改变配体特异性 NMDAR 的离子渗透性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 根据这个新亚基的模式，我们假设 NR3B 亚基可能发挥 在运动神经元功能中发挥核心作用，例如在维持 细胞内钙稳态，并可以解释观察到的差异 NMDAR 脊髓与脑中的药理学。此外，我们建议 NR3B 的正常表达、定位或加工受到破坏 亚基可能导致运动神经元的特定变性，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： 具体目标 1. NR3B 亚基表达改变 NMDA 的机制 将描述受体功能。为此，分子概况和 脊髓运动神经元 NMDA 受体的功能特性 将被表征。特别是，我们将评估 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. 将生成 NR3B-null 小鼠品系并对其进行评估 运动神经元可能发生病理变化。长期目标包括 NR3B相关运动神经元变性小鼠模型的开发 疾病。