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Structural mechanism of voltage-gated sodium channel slow inactivation

Author

Listed:
  • Huiwen Chen

    (Northeast Agricultural University
    Chinese Academy of Sciences)

  • Zhanyi Xia

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Jie Dong

    (Peking University Health Science Center)

  • Bo Huang

    (Beijing StoneWise Technology Co Ltd.)

  • Jiangtao Zhang

    (Chinese Academy of Sciences
    Huazhong University of Science and Technology)

  • Feng Zhou

    (Beijing StoneWise Technology Co Ltd.)

  • Rui Yan

    (Chinese Academy of Sciences
    Huazhong University of Science and Technology)

  • Yiqiang Shi

    (Peking University Health Science Center)

  • Jianke Gong

    (Huazhong University of Science and Technology)

  • Juquan Jiang

    (Northeast Agricultural University)

  • Zhuo Huang

    (Peking University Health Science Center)

  • Daohua Jiang

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

Abstract

Voltage-gated sodium (NaV) channels mediate a plethora of electrical activities. NaV channels govern cellular excitability in response to depolarizing stimuli. Inactivation is an intrinsic property of NaV channels that regulates cellular excitability by controlling the channel availability. The fast inactivation, mediated by the Ile-Phe-Met (IFM) motif and the N-terminal helix (N-helix), has been well-characterized. However, the molecular mechanism underlying NaV channel slow inactivation remains elusive. Here, we demonstrate that the removal of the N-helix of NaVEh (NaVEhΔN) results in a slow-inactivated channel, and present cryo-EM structure of NaVEhΔN in a potential slow-inactivated state. The structure features a closed activation gate and a dilated selectivity filter (SF), indicating that the upper SF and the inner gate could serve as a gate for slow inactivation. In comparison to the NaVEh structure, NaVEhΔN undergoes marked conformational shifts on the intracellular side. Together, our results provide important mechanistic insights into NaV channel slow inactivation.

Suggested Citation

  • Huiwen Chen & Zhanyi Xia & Jie Dong & Bo Huang & Jiangtao Zhang & Feng Zhou & Rui Yan & Yiqiang Shi & Jianke Gong & Juquan Jiang & Zhuo Huang & Daohua Jiang, 2024. "Structural mechanism of voltage-gated sodium channel slow inactivation," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48125-3
    DOI: 10.1038/s41467-024-48125-3
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    References listed on IDEAS

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