IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-48125-3.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-48125-3
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-024-48125-3?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Yue Li & Tian Yuan & Bo Huang & Feng Zhou & Chao Peng & Xiaojing Li & Yunlong Qiu & Bei Yang & Yan Zhao & Zhuo Huang & Daohua Jiang, 2023. "Structure of human NaV1.6 channel reveals Na+ selectivity and pore blockade by 4,9-anhydro-tetrodotoxin," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    2. Daohua Jiang & Tamer M. Gamal El-Din & Christopher Ing & Peilong Lu & Régis Pomès & Ning Zheng & William A. Catterall, 2018. "Structural basis for gating pore current in periodic paralysis," Nature, Nature, vol. 557(7706), pages 590-594, May.
    3. Altin Sula & Jennifer Booker & Leo C. T. Ng & Claire E. Naylor & Paul G. DeCaen & B. A. Wallace, 2017. "The complete structure of an activated open sodium channel," Nature Communications, Nature, vol. 8(1), pages 1-9, April.
    4. Xu Zhang & Wenlin Ren & Paul DeCaen & Chuangye Yan & Xiao Tao & Lin Tang & Jingjing Wang & Kazuya Hasegawa & Takashi Kumasaka & Jianhua He & Jiawei Wang & David E. Clapham & Nieng Yan, 2012. "Crystal structure of an orthologue of the NaChBac voltage-gated sodium channel," Nature, Nature, vol. 486(7401), pages 130-134, June.
    5. Jiangtao Zhang & Yiqiang Shi & Junping Fan & Huiwen Chen & Zhanyi Xia & Bo Huang & Juquan Jiang & Jianke Gong & Zhuo Huang & Daohua Jiang, 2022. "N-type fast inactivation of a eukaryotic voltage-gated sodium channel," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    6. Jian Payandeh & Tamer M. Gamal El-Din & Todd Scheuer & Ning Zheng & William A. Catterall, 2012. "Crystal structure of a voltage-gated sodium channel in two potentially inactivated states," Nature, Nature, vol. 486(7401), pages 135-139, June.
    7. Luis G. Cuello & Vishwanath Jogini & D. Marien Cortes & Eduardo Perozo, 2010. "Structural mechanism of C-type inactivation in K+ channels," Nature, Nature, vol. 466(7303), pages 203-208, July.
    8. Katsumasa Irie & Takushi Shimomura & Yoshinori Fujiyoshi, 2012. "The C-terminal helical bundle of the tetrameric prokaryotic sodium channel accelerates the inactivation rate," Nature Communications, Nature, vol. 3(1), pages 1-8, January.
    9. Jian Payandeh & Todd Scheuer & Ning Zheng & William A. Catterall, 2011. "The crystal structure of a voltage-gated sodium channel," Nature, Nature, vol. 475(7356), pages 353-358, July.
    10. Chen Fan & Nattakan Sukomon & Emelie Flood & Jan Rheinberger & Toby W. Allen & Crina M. Nimigean, 2020. "Ball-and-chain inactivation in a calcium-gated potassium channel," Nature, Nature, vol. 580(7802), pages 288-293, April.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Katsumasa Irie & Yoshinori Oda & Takashi Sumikama & Atsunori Oshima & Yoshinori Fujiyoshi, 2023. "The structural basis of divalent cation block in a tetrameric prokaryotic sodium channel," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    2. Cheng Zhao & Yuan Xie & Lizhen Xu & Fan Ye & Ximing Xu & Wei Yang & Fan Yang & Jiangtao Guo, 2022. "Structures of a mammalian TRPM8 in closed state," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    3. Jiangtao Zhang & Yiqiang Shi & Junping Fan & Huiwen Chen & Zhanyi Xia & Bo Huang & Juquan Jiang & Jianke Gong & Zhuo Huang & Daohua Jiang, 2022. "N-type fast inactivation of a eukaryotic voltage-gated sodium channel," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    4. Mingfeng Zhang & Yuanyue Shan & Duanqing Pei, 2023. "Mechanism underlying delayed rectifying in human voltage-mediated activation Eag2 channel," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    5. Jian Huang & Xiao Fan & Xueqin Jin & Sooyeon Jo & Hanxiong Bear Zhang & Akie Fujita & Bruce P. Bean & Nieng Yan, 2023. "Cannabidiol inhibits Nav channels through two distinct binding sites," Nature Communications, Nature, vol. 14(1), pages 1-9, December.
    6. Lige Tonggu & Goragot Wisedchaisri & Tamer M. Gamal El-Din & Michael J. Lenaeus & Matthew M. Logan & Tatsuya Toma & Justin Bois & Ning Zheng & William A. Catterall, 2024. "Dual receptor-sites reveal the structural basis for hyperactivation of sodium channels by poison-dart toxin batrachotoxin," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    7. Chiung-Wei Huang & Hsing-Jung Lai & Po-Yuan Huang & Ming-Jen Lee & Chung-Chin Kuo, 2016. "The Biophysical Basis Underlying Gating Changes in the p.V1316A Mutant Nav1.7 Channel and the Molecular Pathogenesis of Inherited Erythromelalgia," PLOS Biology, Public Library of Science, vol. 14(9), pages 1-31, September.
    8. Xingya Li & Gengping Jiang & Meipeng Jian & Chen Zhao & Jue Hou & Aaron W. Thornton & Xinyi Zhang & Jefferson Zhe Liu & Benny D. Freeman & Huanting Wang & Lei Jiang & Huacheng Zhang, 2023. "Construction of angstrom-scale ion channels with versatile pore configurations and sizes by metal-organic frameworks," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    9. Qiurong Wu & Jian Huang & Xiao Fan & Kan Wang & Xueqin Jin & Gaoxingyu Huang & Jiaao Li & Xiaojing Pan & Nieng Yan, 2023. "Structural mapping of Nav1.7 antagonists," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    10. Lilia Leisle & Kin Lam & Sepehr Dehghani-Ghahnaviyeh & Eva Fortea & Jason D. Galpin & Christopher A. Ahern & Emad Tajkhorshid & Alessio Accardi, 2022. "Backbone amides are determinants of Cl− selectivity in CLC ion channels," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    11. Yue Li & Tian Yuan & Bo Huang & Feng Zhou & Chao Peng & Xiaojing Li & Yunlong Qiu & Bei Yang & Yan Zhao & Zhuo Huang & Daohua Jiang, 2023. "Structure of human NaV1.6 channel reveals Na+ selectivity and pore blockade by 4,9-anhydro-tetrodotoxin," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    12. Jeroen I Stas & Elke Bocksteins & Alain J Labro & Dirk J Snyders, 2015. "Modulation of Closed−State Inactivation in Kv2.1/Kv6.4 Heterotetramers as Mechanism for 4−AP Induced Potentiation," PLOS ONE, Public Library of Science, vol. 10(10), pages 1-21, October.
    13. Ayumi Sumino & Takashi Sumikama & Mikihiro Shibata & Katsumasa Irie, 2023. "Voltage sensors of a Na+ channel dissociate from the pore domain and form inter-channel dimers in the resting state," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    14. Zhihui He & Yonghui Zhao & Michael J. Rau & James A. J. Fitzpatrick & Rajan Sah & Hongzhen Hu & Peng Yuan, 2023. "Structural and functional analysis of human pannexin 2 channel," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    15. Purushotham Selvakumar & Ana I. Fernández-Mariño & Nandish Khanra & Changhao He & Alice J. Paquette & Bing Wang & Ruiqi Huang & Vaughn V. Smider & William J. Rice & Kenton J. Swartz & Joel R. Meyerson, 2022. "Structures of the T cell potassium channel Kv1.3 with immunoglobulin modulators," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    16. Ahmed Rohaim & Bram J. A. Vermeulen & Jing Li & Felix Kümmerer & Federico Napoli & Lydia Blachowicz & João Medeiros-Silva & Benoît Roux & Markus Weingarth, 2022. "A distinct mechanism of C-type inactivation in the Kv-like KcsA mutant E71V," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    17. Ruo-Xu Gu & Bert L. Groot, 2023. "Central cavity dehydration as a gating mechanism of potassium channels," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    18. Adam Lewis & Vilius Kurauskas & Marco Tonelli & Katherine Henzler-Wildman, 2021. "Ion-dependent structure, dynamics, and allosteric coupling in a non-selective cation channel," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    19. Madeleine R. Wilcox & Aparna Nigam & Nathan G. Glasgow & Chamali Narangoda & Matthew B. Phillips & Dhilon S. Patel & Samaneh Mesbahi-Vasey & Andreea L. Turcu & Santiago Vázquez & Maria G. Kurnikova & , 2022. "Inhibition of NMDA receptors through a membrane-to-channel path," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    20. Ying Wang & Jianxun Mi & Ka Lu & Yanxin Lu & KeWei Wang, 2015. "Comparison of Gating Properties and Use-Dependent Block of Nav1.5 and Nav1.7 Channels by Anti-Arrhythmics Mexiletine and Lidocaine," PLOS ONE, Public Library of Science, vol. 10(6), pages 1-20, June.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48125-3. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.