IDEAS home Printed from https://ideas.repec.org/a/plo/pbio00/1002561.html
   My bibliography  Save this article

The Biophysical Basis Underlying Gating Changes in the p.V1316A Mutant Nav1.7 Channel and the Molecular Pathogenesis of Inherited Erythromelalgia

Author

Listed:
  • Chiung-Wei Huang
  • Hsing-Jung Lai
  • Po-Yuan Huang
  • Ming-Jen Lee
  • Chung-Chin Kuo

Abstract

The Nav1.7 channel critically contributes to the excitability of sensory neurons, and gain-of-function mutations of this channel have been shown to cause inherited erythromelalgia (IEM) with neuropathic pain. In this study, we report a case of a severe phenotype of IEM caused by p.V1316A mutation in the Nav1.7 channel. Mechanistically, we first demonstrate that the Navβ4 peptide acts as a gating modifier rather than an open channel blocker competing with the inactivating peptide to give rise to resurgent currents in the Nav1.7 channel. Moreover, there are two distinct open and two corresponding fast inactivated states in the genesis of resurgent Na+ currents. One is responsible for the resurgent route and practically existent only in the presence of Navβ4 peptide, whereas the other is responsible for the “silent” route of recovery from inactivation. In this regard, the p.V1316A mutation makes hyperpolarization shift in the activation curve, and depolarization shift in the inactivation curve, vividly uncoupling inactivation from activation. In terms of molecular gating operation, the most important changes caused by the p.V1316A mutation are both acceleration of the transition from the inactivated states to the activated states and deceleration of the reverse transition, resulting in much larger sustained as well as resurgent Na+ currents. In summary, the genesis of the resurgent currents in the Nav1.7 channel is ascribable to the transient existence of a distinct and novel open state promoted by the Navβ4 peptide. In addition, S4–5 linker in domain III where V1316 is located seems to play a critical role in activation–inactivation coupling, chiefly via direct modulation of the transitional kinetics between the open and the inactivated states. The sustained and resurgent Na+ currents may therefore be correlatively enhanced by specific mutations involving this linker and relevant regions, and thus marked hyperexcitability in corresponding neural tissues as well as IEM symptomatology.Mutations in the Nav1.7 sodium channel cause idiopathic erythromelalgia. This study shows that the pathogenic resurgent sodium currents arise via modification of gating behavior rather than via competing pore block by the Navβ4 peptide.Author Summary: The gain-of-function mutation (p.V1316A) of the Nav1.7 channel causes inherited erythromelalgia (IEM), a disease characterized by extremely enhanced activity in relevant neural tissues that results in neuropathic pain. We found that the p.V1316A mutation alters the basic gating properties of the channel, leading to increased sustained currents during membrane depolarization and resurgent currents during repolarization. Neurons expressing these mutant channels are more difficult to maintain in a hyperpolarized state and are thus more excitable. We demonstrate that there is very likely a distinct set of open/inactivated (O/I) states responsible for the genesis of resurgent currents. We show that the p.V1316A mutation chiefly accelerates the I to O transition in this set, but also decelerates the transitions between different sets of O/I states, to cause the channel gating and cellular excitability changes. Contrary to the conventional view, we find that the Navβ4 peptide, a key element responsible for sizable resurgent currents, does not seem to act as a pore blocker that competes with the inactivation peptide. Instead, we show that it acts as a gating modifier of the Nav1.7 channel. Thus, the DIII/S4–5 linker, where V1316 is located, may play a critical role not only in O/I coupling but also in the couplings between different sets of O/I in the Nav1.7 channel.

Suggested Citation

  • 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.
  • Handle: RePEc:plo:pbio00:1002561
    DOI: 10.1371/journal.pbio.1002561
    as

    Download full text from publisher

    File URL: https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.1002561
    Download Restriction: no

    File URL: https://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.1002561&type=printable
    Download Restriction: no

    File URL: https://libkey.io/10.1371/journal.pbio.1002561?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. 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.
    2. 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.
    3. James J. Cox & Frank Reimann & Adeline K. Nicholas & Gemma Thornton & Emma Roberts & Kelly Springell & Gulshan Karbani & Hussain Jafri & Jovaria Mannan & Yasmin Raashid & Lihadh Al-Gazali & Henan Hama, 2006. "An SCN9A channelopathy causes congenital inability to experience pain," Nature, Nature, vol. 444(7121), pages 894-898, December.
    4. Marcel P. Goldschen-Ohm & Deborah L. Capes & Kevin M. Oelstrom & Baron Chanda, 2013. "Multiple pore conformations driven by asynchronous movements of voltage sensors in a eukaryotic sodium channel," Nature Communications, Nature, vol. 4(1), pages 1-10, June.
    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. 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.
    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. 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.
    5. 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.
    6. 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.
    7. 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.
    8. 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.
    9. 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.
    10. 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.
    11. Girolamo Di Maio & Ines Villano & Ciro Rosario Ilardi & Antonietta Messina & Vincenzo Monda & Ashlei Clara Iodice & Chiara Porro & Maria Antonietta Panaro & Sergio Chieffi & Giovanni Messina & Marcell, 2023. "Mechanisms of Transmission and Processing of Pain: A Narrative Review," IJERPH, MDPI, vol. 20(4), pages 1-19, February.
    12. 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.
    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. Noel G. Panagiotides & Fritz Zimprich & Klaus Machold & Oliver Schlager & Markus Müller & Sebastian Ertl & Henriette Löffler-Stastka & Renate Koppensteiner & Patricia P. Wadowski, 2023. "A Case of Autoimmune Small Fiber Neuropathy as Possible Post COVID Sequelae," IJERPH, MDPI, vol. 20(6), pages 1-12, March.
    15. 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.
    16. Tianbo Li & Gang Lu & Eugene Y Chiang & Tania Chernov-Rogan & Jane L Grogan & Jun Chen, 2017. "High-throughput electrophysiological assays for voltage gated ion channels using SyncroPatch 768PE," PLOS ONE, Public Library of Science, vol. 12(7), pages 1-18, July.
    17. 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.

    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:plo:pbio00:1002561. 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: plosbiology (email available below). General contact details of provider: https://journals.plos.org/plosbiology/ .

    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.