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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
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    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. 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.
    4. 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.
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