美国冷泉港实验室Hiro Furukawa小组在研究中取得进展。他们开发出NMDA受体的电导控制和神经类固醇结合机制。2025年10月29日，国际知名学术期刊《自然》发表了这一成果。

在这里，研究组报告了电导水平是由异四聚体神经元通道GluN1a-2B n -甲基-D-天冬氨酸受体（NMDAR）中形成孔的跨膜螺旋的弯曲模式控制的。他们的单粒子电子冷冻显微镜（cryo-EM）分析表明，一种内源性神经类固醇和合成的正变构调节剂（PAM） 24s -羟基胆固醇（24S-HC）结合在GluN2B亚基的近膜袋上，并稳定了GluN1a M3和GluN2B M3的成孔螺旋弯曲以扩大通道孔的完全开门构象。相比之下，EU1622-240与GluN1a中相同的GluN2B近膜袋和不同的GluN1a近膜袋结合，以稳定亚开放状态，只有GluN2B M3的螺旋弯曲。与栅极打开的不同程度一致，在24S-HC和EU1622-240存在时，单通道记录主要显示出全导和亚导状态。另一类神经类固醇，孕烯醇酮硫酸盐，与类似的GluN2B口袋结合，但两个分子同时结合，揭示了不同的神经类固醇识别模式。他们的研究表明，近膜袋是调节NMDAR电导水平的关键结构枢纽。

研究人员表示，离子通道活动反映了开放概率和统一电导率的结合。许多通道显示亚电导状态，可调节信号强度，但控制电导水平的结构机制仍不完全清楚。

附：英文原文

Title: Mechanism of conductance control and neurosteroid binding in NMDA receptors

Author: Kang, Hyunook, Steigerwald, Ruben, Ullman, Elijah Z., Epstein, Max, Paladugu, Srinu, Liotta, Dennis C., Traynelis, Stephen F., Furukawa, Hiro

Issue&Volume: 2025-10-29

Abstract: Ion-channel activity reflects a combination of open probability and unitary conductance1. Many channels display subconductance states that modulate signalling strength2,3, yet the structural mechanisms governing conductance levels remain incompletely understood. Here we report that conductance levels are controlled by the bending patterns of pore-forming transmembrane helices in the heterotetrameric neuronal channel GluN1a-2B N-methyl-D-aspartate receptor (NMDAR). Our single-particle electron cryomicroscopy (cryo-EM) analyses demonstrate that an endogenous neurosteroid and synthetic positive allosteric modulator (PAM), 24S-hydroxycholesterol (24S-HC), binds to a juxtamembrane pocket in the GluN2B subunit and stabilizes the fully open-gate conformation, where GluN1a M3 and GluN2B M3′ pore-forming helices are bent to dilate the channel pore. By contrast, EU1622-240 binds to the same GluN2B juxtamembrane pocket and a distinct juxtamembrane pocket in GluN1a to stabilize a sub-open state whereby only the GluN2B M3′ helix is bent. Consistent with the varying extents of gate opening, the single-channel recordings predominantly show full-conductance and subconductance states in the presence of 24S-HC and EU1622-240, respectively. Another class of neurosteroid, pregnenolone sulfate, engages a similar GluN2B pocket, but two molecules bind simultaneously, revealing a diverse neurosteroid recognition pattern. Our study identifies that the juxtamembrane pockets are critical structural hubs for modulating conductance levels in NMDAR.

DOI: 10.1038/s41586-025-09695-4

Source: https://www.nature.com/articles/s41586-025-09695-4