核心要点
- 问题/背景
- 这篇 Nature Neuroscience 论文解析 NMDA 受体为什么既能让 Ca2+ 进入神经元、又会被 Mg2+ 以电压依赖方式阻塞。作者结合单颗粒 cryo-EM、分子动力学和电生理，提出 Ca2+ 通过选择性滤器时发生部分脱水，而 Mg2+ 保持水合并停留在滤器外侧水网络中形成通道阻塞；滤器周围脂质网络还会影响 Mg2+ 结合的电压依赖稳定性。它值得收录，因为它把 Hebbian 可塑性、学习与记忆的经典“巧合检测器”机制...
原始摘要与中文对照
中文对照翻译
赫布神经可塑性被认为是学习和记忆的细胞基础，它可以通过突触前神经递质释放和突触后去极化时Ca内流的巧合检测而发生。在分子水平上，这由N-甲基-D-天冬氨酸型谷氨酸受体介导，该受体结合谷氨酸和甘氨酸，并在膜去极化期间Mg通道阻滞解除后促进Ca内流。然而，N-甲基-D-天冬氨酸型谷氨酸受体中Ca渗透性和Mg阻滞的结构机制尚未完全阐明。在本研究中，我们利用单颗粒冷冻电子显微镜技术证明，Ca通过阳离子选择性滤器狭窄收缩处的渗透涉及部分脱水，这由多个Ca结合位点所证实。相比之下，Mg通过水网络结合在选择性滤器外部并保持水合状态，从而充当通道阻滞剂。此外，选择性滤器周围的脂质网络以电压依赖性方式影响Mg结合的稳定性。我们的研究详细阐述了启动神经可塑性所必需的跨膜化学过程。
原始摘要
Hebbian neuroplasticity, which is thought to be a cellular substrate of learning and memory, can occur by means of coincidental detection of presynaptic neurotransmitter release and Ca influx upon postsynaptic depolarization. This is mediated at a molecular level by N -methyl- D -aspartate-type glutamate receptors, which bind glutamate and glycine and facilitate Ca influx upon relief of Mg channel block during membrane depolarization. However, the structural mechanism underlying Ca permeability and Mg blockade in N -methyl- D -aspartate-type glutamate receptors has yet to be fully elucidated. Here we demonstrate using single-particle cryo-electron microscopy that Ca permeation through the narrow constriction of the cation selectivity filter involves partial dehydration, as evidenced by several Ca binding sites. In contrast, Mg binds outside of the selectivity filter through a water network and remains hydrated, thereby acting as a channel blocker. Furthermore, the lipid network around the selectivity filter influences the stability of Mg binding in a voltage-dependent manner. Our study details the transmembrane chemistry essential for initiating neuroplasticity.