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对NMDA受体激活的冷EM快照照照亮了连续的重新安排

Jamie A Abbott¹, Junhoe Kim², Beiying Liu¹

¹Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, SUNY, Buffalo, NY 14203, USA.

Science advances

|September 24, 2025

概括

正规的N-甲基-D-酸盐受体 (NMDARs) 对于神经系统的功能至关重要. 这项研究揭示了使用冷电磁和电生理学的NMDAR通道开放机制,详细介绍了关门期间的结构变化.

科学领域:

神经科学是一个神经科学.
结构生物学结构生物学
生物物理学的生物物理.

背景情况:

N-甲基-D-酸盐受体 (NMDARs) 是关闭谷氨酸的离子通道,对神经元功能至关重要.
NMDAR功能涉及关闭和开放状态之间的过渡,影响激发性神经传递.

研究的目的:

阐明NMDAR通道封锁背后的结构机制.
捕捉和描述NMDARs的不同激活状态.

主要方法:

单粒子冷电子显微镜 (cryo-EM) 用于可视化受体结构.
单通道电生理学和统计建模来分析门的动力学.
利用了高开放概率的NMDARs (GluN1/GluN2A) 和特定的突变/配体.

主要成果:

三种不同的NMDAR激活状态被冷-EM捕获,显示出独特的M3螺旋形状.
电生理学和建模将这些结构与关门过程联系起来.
确定了涉及D2-M3连接器,M1前螺旋和M4前循环在开放状态下的稳定机制.

结论:

NMDAR通道的开放是由M3螺旋曲驱动的,从而创建了一个暂时的开放状态.
特定的分子相互作用使NMDAR通道在其开放的形状中稳定.
这提供了对NMDAR门的详细结构和机制的理解.

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Cryo-electron Microscopy

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Conventional electron microscopy (EM) involves dehydration, fixation, and staining of biological samples, which distorts the native state of biological molecules and results in several artifacts. Also, the high-energy electron beam damages the sample and makes it difficult to obtain high-resolution images. These issues can be addressed using cryo-EM, which uses frozen samples and gentler electron beams. The technique was developed by Jacques Dubochet, Joachim Frank, and Richard Henderson, for...