IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-34359-6.html
   My bibliography  Save this article

An allosteric modulator activates BK channels by perturbing coupling between Ca2+ binding and pore opening

Author

Listed:
  • Guohui Zhang

    (Washington University)

  • Xianjin Xu

    (University of Missouri – Columbia
    University of Missouri – Columbia
    University of Missouri – Columbia
    University of Missouri – Columbia)

  • Zhiguang Jia

    (University of Massachusetts
    University of Massachusetts)

  • Yanyan Geng

    (University of Miami Miller School of Medicine)

  • Hongwu Liang

    (Washington University)

  • Jingyi Shi

    (Washington University)

  • Martina Marras

    (Washington University)

  • Carlota Abella

    (Washington University)

  • Karl L. Magleby

    (University of Miami Miller School of Medicine)

  • Jonathan R. Silva

    (Washington University)

  • Jianhan Chen

    (University of Massachusetts
    University of Massachusetts)

  • Xiaoqin Zou

    (University of Missouri – Columbia
    University of Missouri – Columbia
    University of Missouri – Columbia
    University of Missouri – Columbia)

  • Jianmin Cui

    (Washington University)

Abstract

BK type Ca2+-activated K+ channels activate in response to both voltage and Ca2+. The membrane-spanning voltage sensor domain (VSD) activation and Ca2+ binding to the cytosolic tail domain (CTD) open the pore across the membrane, but the mechanisms that couple VSD activation and Ca2+ binding to pore opening are not clear. Here we show that a compound, BC5, identified from in silico screening, interacts with the CTD-VSD interface and specifically modulates the Ca2+ dependent activation mechanism. BC5 activates the channel in the absence of Ca2+ binding but Ca2+ binding inhibits BC5 effects. Thus, BC5 perturbs a pathway that couples Ca2+ binding to pore opening to allosterically affect both, which is further supported by atomistic simulations and mutagenesis. The results suggest that the CTD-VSD interaction makes a major contribution to the mechanism of Ca2+ dependent activation and is an important site for allosteric agonists to modulate BK channel activation.

Suggested Citation

  • Guohui Zhang & Xianjin Xu & Zhiguang Jia & Yanyan Geng & Hongwu Liang & Jingyi Shi & Martina Marras & Carlota Abella & Karl L. Magleby & Jonathan R. Silva & Jianhan Chen & Xiaoqin Zou & Jianmin Cui, 2022. "An allosteric modulator activates BK channels by perturbing coupling between Ca2+ binding and pore opening," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34359-6
    DOI: 10.1038/s41467-022-34359-6
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-34359-6
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-022-34359-6?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. Zhiguang Jia & Mahdieh Yazdani & Guohui Zhang & Jianmin Cui & Jianhan Chen, 2018. "Hydrophobic gating in BK channels," Nature Communications, Nature, vol. 9(1), pages 1-8, December.
    2. Jingyi Shi & Gayathri Krishnamoorthy & Yanwu Yang & Lei Hu & Neha Chaturvedi & Dina Harilal & Jun Qin & Jianmin Cui, 2002. "Mechanism of magnesium activation of calcium-activated potassium channels," Nature, Nature, vol. 418(6900), pages 876-880, August.
    3. Richard K. Hite & Xiao Tao & Roderick MacKinnon, 2017. "Structural basis for gating the high-conductance Ca2+-activated K+ channel," Nature, Nature, vol. 541(7635), pages 52-57, January.
    4. Xiao Tao & Richard K. Hite & Roderick MacKinnon, 2017. "Cryo-EM structure of the open high-conductance Ca2+-activated K+ channel," Nature, Nature, vol. 541(7635), pages 46-51, January.
    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. 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.
    2. Tobias Raisch & Andreas Brockmann & Ulrich Ebbinghaus-Kintscher & Jörg Freigang & Oliver Gutbrod & Jan Kubicek & Barbara Maertens & Oliver Hofnagel & Stefan Raunser, 2021. "Small molecule modulation of the Drosophila Slo channel elucidated by cryo-EM," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    3. Navid Paknejad & Vinay Sapuru & Richard K. Hite, 2023. "Structural titration reveals Ca2+-dependent conformational landscape of the IP3 receptor," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    4. Davide Caprini & Francesco Battista & Paweł Zajdel & Giovanni Di Muccio & Carlo Guardiani & Benjamin Trump & Marcus Carter & Andrey A. Yakovenko & Eder Amayuelas & Luis Bartolomé & Simone Meloni & Yar, 2024. "Bubbles enable volumetric negative compressibility in metastable elastocapillary systems," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    5. Yu-Li Ni & Ai-Seon Kuan & Tsung-Yu Chen, 2014. "Activation and Inhibition of TMEM16A Calcium-Activated Chloride Channels," PLOS ONE, Public Library of Science, vol. 9(1), pages 1-12, January.
    6. Johansen B. Amin & Miaomiao He & Ramesh Prasad & Xiaoling Leng & Huan-Xiang Zhou & Lonnie P. Wollmuth, 2023. "Two gates mediate NMDA receptor activity and are under subunit-specific regulation," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    7. Carlos A. Z. Bassetto & Flavio Costa & Carlo Guardiani & Francisco Bezanilla & Alberto Giacomello, 2023. "Noncanonical electromechanical coupling paths in cardiac hERG potassium channel," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    8. Gonçalo Paulo & Ke Sun & Giovanni Di Muccio & Alberto Gubbiotti & Blasco Morozzo della Rocca & Jia Geng & Giovanni Maglia & Mauro Chinappi & Alberto Giacomello, 2023. "Hydrophobically gated memristive nanopores for neuromorphic applications," Nature Communications, Nature, vol. 14(1), pages 1-9, 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_s41467-022-34359-6. 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.