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Structural basis of the neuronal M-current generated by an asymmetric KCNQ2/3 assembly

Cell Research (2026) Cite this article

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Dear Editor,

The voltage-gated KCNQ2/3 heteromer channel underlies the neuronal M-current, a slow-activating potassium current that stabilizes membrane potential and prevents neuronal hyperexcitability.1 Mutations in KCNQ2 or KCNQ3 disrupt this current, causing epileptic encephalopathies and implicating channel dysfunction in neuropathic pain and auditory disorders.2 Despite differences in gating, trafficking, and phosphatidylinositol 4,5-bisphosphate (PIP₂) sensitivity in homomers, KCNQ2/3 heteromers generate finely tuned currents, implying emergent structural properties unique to the heterocomplex. However, the subunit stoichiometry (KCNQ2:KCNQ3) remains controversial.3

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Fig. 1: Assembly and activation of the KCNQ2/3 heteromer.
The alternative text for this image may have been generated using AI.

Data availability

The atomic coordinates and cryo-EM density maps for KCNQ2/3/3/3apo (accession codes: 9X5J and EMDB-66589) and KCNQ2/3/3/3XEN1101/PIP2 (accession codes: 9×65 and EMDB-66607) have been deposited in the Protein Data Bank and Electron Microscopy Data Bank, respectively. Source data are provided with this paper.

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Acknowledgements

We thank the Cryo-EM center of Shuimu BioSciences for our cryo-EM work and their help with cryo-EM data collection. This work was supported by School of Basic Medical Sciences, Nanchang University. J.Z. was supported by the National Natural Science Foundation of China (32271260), the CAS “Light of West China” Program (xbzg-zdsys-202005), the Shenzhen Science and Technology Program (JCYJ20220818103017036 and KJZD20240903102205008) and the Jiangxi Province Natural Science Foundation (20224ACB206046). P.H. was supported by the National Natural Science Foundation of China (32171221), MOST-FDCT (0006/2021/AMJ), FDCT (0074/2022/A2, 0098/2023/RIA2, 0009/2025/RDP, and 0003/2025/NRP), and Guangdong Province Pearl River Talent Program (2024QN11Y354). B.H. acknowledges support from the Science and Technology Research Project of Jiangxi Provincial Department of Education (GJJ2201447) and the Jiangxi Provincial Natural Science Foundation (20252BAC240521).

Author information

Author notes

  1. These authors contributed equally: Xinyu Cheng, Shuangyan Wan, Dexiang Jiang, Hangyu Zhang, Bin Hu.

Authors and Affiliations

  1. The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, School of Basic Medical Sciences, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China

    Xinyu Cheng, Shuangyan Wan, Tong Che, Yuanpeng Chen & Jin Zhang

  2. Jiangxi Provincial Key Laboratory of Tumor Biology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China

    Xinyu Cheng, Shuangyan Wan, Tong Che, Yuanpeng Chen & Jin Zhang

  3. Dr. Neher’s Biophysics Laboratory for Innovative Drug Discovery; State Key Laboratory of Mechanism and Quality of Chinese Medicine; School of Pharmacy, Faculty of Medicine; Faculty of Chinese Medicine, Macau University of Science and Technology, Macau SAR, China

    Dexiang Jiang, Hangyu Zhang, Zhuo Zhou, Chenxin Xiao, Ling Zhong & Panpan Hou

  4. Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases of Ministry of Education, School of Basic Medical Sciences, Gannan Medical University, Ganzhou, Jiangxi, China

    Bin Hu

  5. Shenzhen Crystalo Biopharmaceutical Co., Ltd, Shenzhen, Guangdong, China

    Weiwei Nan & Yuting Zhang

  6. Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China

    Bing Xiong

  7. Macau University of Science and Technology Innovation Technology Research Institute, Hengqin, Guangdong, China

    Panpan Hou

Authors
  1. Xinyu Cheng
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  2. Shuangyan Wan
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  9. Zhuo Zhou
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  14. Panpan Hou
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  15. Jin Zhang
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Contributions

P.H. and J.Z. conceived the project, designed the research and supervised the study. X.C., S.W., D.J., H.Z., B.H., Y.C., W.N., Z.Z., C.X., L.Z., Y.Z., P.H. and J.Z. performed the experiments. X.C., S.W., D.J., H.Z., B.H., T.C., W.N., Z.Z., C.X., L.Z., Y.Z., P.H. and J.Z. analyzed the data. B.X., P.H. and J.Z. provided key intellectual expertise and methodologies. X.C., S.W., D.J., H.Z., B.H., P.H. and J.Z. wrote the manuscript with inputs from all authors.

Corresponding authors

Correspondence to Panpan Hou or Jin Zhang.

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Cheng, X., Wan, S., Jiang, D. et al. Structural basis of the neuronal M-current generated by an asymmetric KCNQ2/3 assembly. Cell Res (2026). https://doi.org/10.1038/s41422-026-01261-5

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