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Structural insights into the progressive recovery of α7 nicotinic acetylcholine receptor from nicotine-induced desensitization

文献类型：期刊论文

作者Liu, Sanling8,9; Chen, Haopeng8; Zhu, Xiaohong7; Ye, Fei6; Zhao, Yue8; Qin, Junlin4,5; Zheng, Yining8; Wang, Xudong8; Zhang, Longhua8; Chen, Huan9
刊名SCIENCE ADVANCES
出版日期2025-10-10
卷号11期号:41页码:16
DOI10.1126/sciadv.adx4432
通讯作者Liu, Sanling(sanling@ustc.edu.cn) ; Hou, Hongwei(qsfctc@163.com) ; Bai, Chen(baichen@momedtech.com.cn) ; Liu, Lei(lliu@mail.tsinghua.edu.cn) ; Tian, Changlin(cltian@ustc.edu.cn)
英文摘要Nicotine is the predominant alkaloid in tobacco leaves and affects the human nervous system by interacting with nicotinic acetylcholine receptors (nAChRs). Chronic nicotine exposure leads to nAChR desensitization, while nicotine withdrawal leads to nAChR recovery. However, detailed molecular mechanisms underlying nicotine-induced nAChR desensitization and its recovery remain elusive. Here, we present cryo-EM structures of the alpha 7 nAChR in complex with nicotine in both an open state and multiple desensitized states. Comparative analyses reveal progressive conformational changes during recovery from nicotine-induced desensitization and show that asymmetric nicotine binding disrupts the symmetry of the channel pore at the 16 ' and 17 ' sites. Integrating these findings with patch-clamp recordings and computational simulations, we identify an agonist-free structure that represents an atypical desensitized state closely resembling the resting conformation of alpha 7 nAChR. These detailed mechanistic studies enhance our understanding of nicotine's effects on alpha 7 nAChRs.
WOS关键词PHARMACOLOGICAL-PROPERTIES ; EXCITATORY INPUTS ; ACH RECEPTORS ; FREE-ENERGY ; ADDICTION ; ACTIVATION ; MECHANISMS ; MODULATION ; PROTEINS ; SUBTYPES
资助项目National Key R&D Program of China[2022YFC3400500] ; National Natural Science Foundation of China[22437005] ; National Natural Science Foundation of China[T2488301] ; Beijing Life Science Academy Scientific Research Program[2023000CA0070] ; Beijing Life Science Academy Scientific Research Program[2024100CA0060] ; Beijing Life Science Academy Scientific Research Program[2023000CC0050] ; Beijing Life Science Academy Scientific Research Program[2024102QPID06] ; Beijing Life Science Academy Scientific Research Program[2024501QPIC05]
WOS研究方向Science & Technology - Other Topics
语种英语
WOS记录号WOS:001591645900024
出版者AMER ASSOC ADVANCEMENT SCIENCE
源URL[http://119.78.100.183/handle/2S10ELR8/321654]  
专题中国科学院上海药物研究所
通讯作者Liu, Sanling; Hou, Hongwei; Bai, Chen; Liu, Lei; Tian, Changlin
作者单位1.Tsinghua Univ, Dept Chem, Beijing, Peoples R China
2.Univ Sci & Technol China, Suzhou Inst Adv Res, Sch Biomed Engn, Suzhou, Jiangsu, Peoples R China
3.Shanghai Jiao Tong Univ, Int Peace Matern & Child Hlth Hosp, Sch Chem & Chem Engn, Natl Ctr Translat Med,Zhangjiang Inst Adv Study, Shanghai, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, Ctr Chem Biol, Shanghai, Peoples R China
5.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou, Peoples R China
6.Zhejiang Sci Tech Univ, Coll Life Sci & Med, Hangzhou, Zhejiang, Peoples R China
7.Chenzhu MoMeD Biotechnol Co Ltd, Hangzhou, Peoples R China
8.Univ Sci & Technol China, Hefei Natl Res Ctr Phys Sci Microscale, Div Life Sci & Med, Anhui Engn Lab Peptide Drug, Hefei, Anhui, Peoples R China
9.Beijing Life Sci Acad, Beijing, Peoples R China
推荐引用方式
GB/T 7714		 Liu, Sanling,Chen, Haopeng,Zhu, Xiaohong,et al. Structural insights into the progressive recovery of α7 nicotinic acetylcholine receptor from nicotine-induced desensitization[J]. SCIENCE ADVANCES,2025,11(41):16.
APA Liu, Sanling.,Chen, Haopeng.,Zhu, Xiaohong.,Ye, Fei.,Zhao, Yue.,...&Tian, Changlin.(2025).Structural insights into the progressive recovery of α7 nicotinic acetylcholine receptor from nicotine-induced desensitization.SCIENCE ADVANCES,11(41),16.
MLA Liu, Sanling,et al."Structural insights into the progressive recovery of α7 nicotinic acetylcholine receptor from nicotine-induced desensitization".SCIENCE ADVANCES 11.41(2025):16.

入库方式： OAI收割

来源：上海药物研究所

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