2026年7月1日，加州大学Ryan E. Hibbs课题组在《自然》杂志发表论文，宣布他们的研究发现纠正先天性重症肌无力相关乙酰胆碱受体缺陷。

以低温电子显微镜、化学生物学和电生理学为主题，研究团队确定了有代表性的CMS突变受体的结构和功能后果。在快速通道疾病相关突变体中，课题组发现了一个由正调节剂靶向的隐变抗压位点，以突变特异性的方式恢复门控。在与慢通道疾病相关的受体突变体中，奎尼丁、氟西汀和瑞波西汀可作为孔阻滞剂；值得注意的是，抗抑郁药瑞波西汀选择性地阻断脱敏受体以一种不依赖突变的方式，表明其具有重新利用的潜力。从机制上讲，快速通道突变使激动剂结合脱离门控，而慢通道突变稳定了异常变宽的脱敏样孔。这些发现揭示了CMS发病机制的统一原则，并为精准治疗提供了框架。

据介绍，神经递质乙酰胆碱与其受体结合在神经细胞连接处的突触后膜上，打开离子通道，允许阳离子流入并启动去极化，从而触发随意的细胞收缩。细胞乙酰胆碱受体的突变通过损害（快速通道）或延长（慢通道）通道开放来破坏这一过程。这些缺陷是先天性肌无力综合征（CMS），其特征是严重的肌肉无力，通常在出生时出现，在某些情况下，发展为瘫痪和死亡。这些致病缺陷的结构机制及其药理学纠正尚不清楚。

附：英文原文

Title: Correcting congenital myasthenia-associated acetylcholine receptor defects

Author: Li, Huanhuan, Mukhtasimova, Nuriya, Teng, Jinfeng, Cavalli, Elfie S., Gu, Xilin, Sello, Jason K., Sine, Steven M., Hibbs, Ryan E.

Issue&Volume: 2026-07-01

Abstract: Voluntary muscle contraction is triggered by the neurotransmitter acetylcholine binding its receptors on the postsynaptic membrane of the neuromuscular junction, opening ion channels that allow cation influx and initiate depolarization1,2,3. Mutations in muscle acetylcholine receptors disrupt this process by either impairing (fast-channel) or prolonging (slow-channel) channel openings1,4. These defects cause congenital myasthenic syndromes (CMS), characterized by severe muscle weakness that is often present at birth and, in some cases, progresses to paralysis and death5,6. The structural mechanisms underlying these pathogenic defects and their pharmacological correction remain unknown. Here, using cryogenic electron microscopy, chemical biology and electrophysiology, we determined the structures and functional consequences of representative CMS mutant receptors with and without drugs. In fast-channel disease-associated mutants, we discovered a cryptic allosteric site targeted by positive modulators that restore gating in a mutation-specific manner. In receptor mutants associated with slow-channel disease, quinidine, fluoxetine and reboxetine act as pore blockers; notably, the antidepressant reboxetine selectively blocks desensitized receptors in a mutation-independent fashion, suggesting repurposing potential. Mechanistically, fast-channel mutations uncouple agonist binding from gating, whereas slow-channel mutations stabilize an abnormally widened, desensitized-like pore. These findings reveal unifying principles of CMS pathogenesis and provide a framework for precision therapies.

DOI: 10.1038/s41586-026-10706-1

Source: https://www.nature.com/articles/s41586-026-10706-1