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Noncanonical electromechanical coupling paths in cardiac hERG potassium channel

Author

Listed:
  • Carlos A. Z. Bassetto

    (The University of Chicago)

  • Flavio Costa

    (Sapienza Università di Roma)

  • Carlo Guardiani

    (Sapienza Università di Roma)

  • Francisco Bezanilla

    (The University of Chicago
    The University of Chicago
    Universidad de Valparaiso)

  • Alberto Giacomello

    (Sapienza Università di Roma)

Abstract

Voltage-gated potassium channels are involved in many physiological processes such as nerve impulse transmission, the heartbeat, and muscle contraction. However, for many of them the molecular determinants of the gating mechanism remain elusive. Here, using a combination of theoretical and experimental approaches, we address this problem focusing on the cardiac hERG potassium channel. Network analysis of molecular dynamics trajectories reveals the presence of a kinematic chain of residues that couples the voltage sensor domain to the pore domain and involves the S4/S1 and S1/S5 subunit interfaces. Mutagenesis experiments confirm the role of these residues and interfaces in the activation and inactivation mechanisms. Our findings demonstrate the presence of an electromechanical transduction path crucial for the non-domain-swapped hERG channel gating that resembles the noncanonical path identified in domain-swapped K+ channels.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36730-7
    DOI: 10.1038/s41467-023-36730-7
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    References listed on IDEAS

    as
    1. João L. Carvalho-de-Souza & Francisco Bezanilla, 2019. "Noncanonical mechanism of voltage sensor coupling to pore revealed by tandem dimers of Shaker," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    2. Michael C. Sanguinetti & Martin Tristani-Firouzi, 2006. "hERG potassium channels and cardiac arrhythmia," Nature, Nature, vol. 440(7083), pages 463-469, March.
    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. Michael David Clark & Gustavo F. Contreras & Rong Shen & Eduardo Perozo, 2020. "Electromechanical coupling in the hyperpolarization-activated K+ channel KAT1," Nature, Nature, vol. 583(7814), pages 145-149, July.
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    Cited by:

    1. Carus H. Y. Lau & Emelie Flood & Mark J. Hunter & Billy J. Williams-Noonan & Karen M. Corbett & Chai-Ann Ng & James C. Bouwer & Alastair G. Stewart & Eduardo Perozo & Toby W. Allen & Jamie I. Vandenbe, 2024. "Potassium dependent structural changes in the selectivity filter of HERG potassium channels," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    2. 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.

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