IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-31526-7.html
   My bibliography  Save this article

Structural and electrophysiological basis for the modulation of KCNQ1 channel currents by ML277

Author

Listed:
  • Katrien Willegems

    (University of British Columbia
    University of British Columbia)

  • Jodene Eldstrom

    (University of British Columbia)

  • Efthimios Kyriakis

    (University of British Columbia)

  • Fariba Ataei

    (University of British Columbia)

  • Harutyun Sahakyan

    (National Institutes for Health)

  • Ying Dou

    (University of British Columbia)

  • Sophia Russo

    (University of British Columbia)

  • Filip Petegem

    (University of British Columbia)

  • David Fedida

    (University of British Columbia)

Abstract

The KCNQ1 ion channel plays critical physiological roles in electrical excitability and K+ recycling in organs including the heart, brain, and gut. Loss of function is relatively common and can cause sudden arrhythmic death, sudden infant death, epilepsy and deafness. Here, we report cryogenic electron microscopic (cryo-EM) structures of Xenopus KCNQ1 bound to Ca2+/Calmodulin, with and without the KCNQ1 channel activator, ML277. A single binding site for ML277 was identified, localized to a pocket lined by the S4-S5 linker, S5 and S6 helices of two separate subunits. Several pocket residues are not conserved in other KCNQ isoforms, explaining specificity. MD simulations and point mutations support this binding location for ML277 in open and closed channels and reveal that prevention of inactivation is an important component of the activator effect. Our work provides direction for therapeutic intervention targeting KCNQ1 loss of function pathologies including long QT interval syndrome and seizures.

Suggested Citation

  • Katrien Willegems & Jodene Eldstrom & Efthimios Kyriakis & Fariba Ataei & Harutyun Sahakyan & Ying Dou & Sophia Russo & Filip Petegem & David Fedida, 2022. "Structural and electrophysiological basis for the modulation of KCNQ1 channel currents by ML277," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31526-7
    DOI: 10.1038/s41467-022-31526-7
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-31526-7
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-022-31526-7?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. Björn C. Schroeder & Siegfried Waldegger & Susanne Fehr & Markus Bleich & Richard Warth & Rainer Greger & Thomas J. Jentsch, 2000. "A constitutively open potassium channel formed by KCNQ1 and KCNE3," Nature, Nature, vol. 403(6766), pages 196-199, January.
    2. Panpan Hou & Jodene Eldstrom & Jingyi Shi & Ling Zhong & Kelli McFarland & Yuan Gao & David Fedida & Jianmin Cui, 2017. "Inactivation of KCNQ1 potassium channels reveals dynamic coupling between voltage sensing and pore opening," Nature Communications, Nature, vol. 8(1), pages 1-11, December.
    3. Panpan Hou & Po Wei Kang & Audrey Deyawe Kongmeneck & Nien-Du Yang & Yongfeng Liu & Jingyi Shi & Xianjin Xu & Kelli McFarland White & Mark A. Zaydman & Marina A. Kasimova & Guiscard Seebohm & Ling Zho, 2020. "Two-stage electro–mechanical coupling of a KV channel in voltage-dependent activation," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    4. Karen Mruk & William R Kobertz, 2009. "Discovery of a Novel Activator of KCNQ1-KCNE1 K+ Channel Complexes," PLOS ONE, Public Library of Science, vol. 4(1), pages 1-9, January.
    Full references (including those not matched with items on IDEAS)

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Demin Ma & Yueming Zheng & Xiaoxiao Li & Xiaoyu Zhou & Zhenni Yang & Yan Zhang & Long Wang & Wenbo Zhang & Jiajia Fang & Guohua Zhao & Panpan Hou & Fajun Nan & Wei Yang & Nannan Su & Zhaobing Gao & Ji, 2023. "Ligand activation mechanisms of human KCNQ2 channel," Nature Communications, Nature, vol. 14(1), pages 1-13, December.

    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. 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.
    2. Karen Mruk & William R Kobertz, 2009. "Discovery of a Novel Activator of KCNQ1-KCNE1 K+ Channel Complexes," PLOS ONE, Public Library of Science, vol. 4(1), pages 1-9, January.
    3. Kamilla Kelemen & Ian D. Greener & Xiaoping Wan & Shankar Parajuli & J. Kevin Donahue, 2022. "Heterogeneous repolarization creates ventricular tachycardia circuits in healed myocardial infarction scar," Nature Communications, Nature, vol. 13(1), pages 1-14, 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:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31526-7. 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.