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Structural basis for hyperpolarization-dependent opening of human HCN1 channel

Author

Listed:
  • Verena Burtscher

    (Washington University School of Medicine
    Washington University School of Medicine)

  • Jonathan Mount

    (Washington University School of Medicine
    Washington University School of Medicine
    Icahn School of Medicine at Mount Sinai)

  • Jian Huang

    (University of Massachusetts)

  • John Cowgill

    (Washington University School of Medicine
    Washington University School of Medicine
    KTH Royal Institute of Technology)

  • Yongchang Chang

    (Washington University School of Medicine
    Washington University School of Medicine)

  • Kathleen Bickel

    (Washington University School of Medicine
    Washington University School of Medicine)

  • Jianhan Chen

    (University of Massachusetts)

  • Peng Yuan

    (Washington University School of Medicine
    Washington University School of Medicine
    Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Baron Chanda

    (Washington University School of Medicine
    Washington University School of Medicine
    Washington University School of Medicine
    Washington University School of Medicine)

Abstract

Hyperpolarization and cyclic nucleotide (HCN) activated ion channels are critical for the automaticity of action potentials in pacemaking and rhythmic electrical circuits in the human body. Unlike most voltage-gated ion channels, the HCN and related plant ion channels activate upon membrane hyperpolarization. Although functional studies have identified residues in the interface between the voltage-sensing and pore domain as crucial for inverted electromechanical coupling, the structural mechanisms for this unusual voltage-dependence remain unclear. Here, we present cryo-electron microscopy structures of human HCN1 corresponding to Closed, Open, and a putative Intermediate state. Our structures reveal that the downward motion of the gating charges past the charge transfer center is accompanied by concomitant unwinding of the inner end of the S4 and S5 helices, disrupting the tight gating interface observed in the Closed state structure. This helix-coil transition at the intracellular gating interface accompanies a concerted iris-like dilation of the pore helices and underlies the reversed voltage dependence of HCN channels.

Suggested Citation

  • Verena Burtscher & Jonathan Mount & Jian Huang & John Cowgill & Yongchang Chang & Kathleen Bickel & Jianhan Chen & Peng Yuan & Baron Chanda, 2024. "Structural basis for hyperpolarization-dependent opening of human HCN1 channel," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49599-x
    DOI: 10.1038/s41467-024-49599-x
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    References listed on IDEAS

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