中国科学院脑科学与智能技术卓越中心竺淑佳等研究人员合作揭示，成年大脑皮层和海马中内源性NMDA受体的组装与结构。该研究于2025年1月23日在线发表于国际一流学术期刊《细胞》。

研究人员表示，大脑皮层和海马是学习和记忆的重要脑区，这些过程依赖于通过N-甲基-D-天冬氨酸受体（NMDAR）介导的活动诱导突触可塑性。然而，内源性NMDAR（eNMDAR）在大脑中的亚基组装和分子结构仍不明晰。

研究人员使用依赖于构象和亚基的抗体，从成年大鼠的大脑皮层和海马中纯化了eNMDAR。通过冷冻电镜（cryo-EM），研究人员解析了三种主要亚型：GluN1-N2A-N2B、GluN1-N2B和GluN1-N2A eNMDAR，分辨率高达4.2 Å。

这三种亚型的粒子比例为9:7:4，表明大约一半的GluN2A和GluN2B亚基被纳入了三重异四聚体中。结构分析揭示了GluN1-N2A-N2B受体从细胞外到跨膜层的非对称结构。此外，GluN1-N2B和GluN1-N2A-N2B受体之间的构象差异揭示了不同eNMDAR亚型之间的独特生物物理特性。

这些研究结果暗示了eNMDAR的结构和功能复杂性，并为基于结构的治疗设计提供了启示，可用于靶向这些eNMDAR进行体内治疗。

附：英文原文

Title: Assembly and architecture of endogenous NMDA receptors in adult cerebral cortex and hippocampus

Author: Ming Zhang, Juan Feng, Chun Xie, Nan Song, Chaozhi Jin, Jian Wang, Qun Zhao, Lihua Zhang, Boshuang Wang, Yidi Sun, Fei Guo, Yang Li, Shujia Zhu

Issue&Volume: 2025-01-23

Abstract: The cerebral cortex and hippocampus are crucial brain regions for learning and memory, which depend on activity-induced synaptic plasticity involving N-methyl--aspartate receptors (NMDARs). However, subunit assembly and molecular architecture of endogenous NMDARs (eNMDARs) in the brain remain elusive. Using conformation- and subunit-dependent antibodies, we purified eNMDARs from adult rat cerebral cortex and hippocampus. Three major subtypes of GluN1-N2A-N2B, GluN1-N2B, and GluN1-N2A eNMDARs were resolved by cryoelectron microscopy (cryo-EM) at the resolution up to 4.2 . The particle ratio of these three subtypes was 9:7:4, indicating that about half of GluN2A and GluN2B subunits are incorporated into the tri-heterotetramers. Structural analysis revealed the asymmetric architecture of the GluN1-N2A-N2B receptor throughout the extracellular to the transmembrane layers. Moreover, the conformational variations between GluN1-N2B and GluN1-N2A-N2B receptors revealed the distinct biophysical properties across different eNMDAR subtypes. Our findings imply the structural and functional complexity of eNMDARs and shed light on structure-based therapeutic design targeting these eNMDARs in vivo.

DOI: 10.1016/j.cell.2025.01.004

Source: https://www.cell.com/cell/abstract/S0092-8674(25)00033-9