NMDA受体连接和开放的分子机制
Tsung-Han Chou1, Max Epstein1, Russell G Fritzemeier2
1W.M. Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
Nature
|July 31, 2024
概括
当甘氨酸和谷氨酸结合时,N-甲基-D-亚斯巴酸受体 (NMDAR) 开放,在其结构中产生张力. 这项研究揭示了NMDAR通道关的分子机制,这对神经元刺激性和神经可塑性至关重要.
科学领域:
- 神经科学
- 分子生物学
- 结构生物学
背景情况:
- 离子型谷氨酸受体,包括N-甲基-D-亚斯巴酸受体 (NMDARs),对神经元刺激性和可塑性至关重要.
- NMDARs是独特的链接通道,需要谷氨酸和甘氨酸来激活.
- NMDAR通道封锁的确切机制仍然难以捉摸,缺乏开放和非开放状态的结构数据.
研究的目的:
- 阐明NMDAR通道封闭的分子机制.
- 通过糖氨酸和谷氨酸激活NMDAR的结构要求.
主要方法:
- 使用电子冷显微镜 (cryo-EM) 来确定GluN1- GluN2B NMDAR的结构.
- 获得了开放状态,apo状态和单链状态的结构.
主要成果:
- NMDAR通道的开放需要在连接体结合域 (LBD) 和跨膜域 (TMD) 之间的紧张,加上细胞外域旋转.
- 由于孔螺旋曲和旋转,开放的NMDAR结构显示了改变的TMD通道对称性 (伪四倍到两倍).
- 单联体结合会产生明显的二极管排列,但不够的LBD-TMD连接器张力来打开通道.
结论:
- 为NMDAR通道封锁提出了一个新的机制框架,强调LBD-TMD链接器张力和域旋转.
- 该框架确定了NMDAR功能的关键决定因素,并建议药物调节的潜在目标.
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