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HCN4 channels sense temperature and determine heart rate responses to heat

Author

Listed:
  • Yuejin Wu

    (Johns Hopkins School of Medicine)

  • Qinchuan Wang

    (Johns Hopkins School of Medicine)

  • Jonathan Granger

    (Johns Hopkins School of Medicine)

  • Oscar Reyes Gaido

    (Johns Hopkins School of Medicine)

  • Gabriel Lopez-Cecetaite

    (Johns Hopkins School of Medicine)

  • Eric Nunez Aguilar

    (Johns Hopkins University School of Medicine)

  • Andreas Ludwig

    (Friedrich-Alexander-Universität Erlangen-Nürnberg)

  • Anna Moroni

    (via Celoria 26)

  • Mario A. Bianchet

    (Johns Hopkins University School of Medicine)

  • Mark E. Anderson

    (Johns Hopkins School of Medicine
    University of Chicago)

Abstract

The hyperpolarization-activated cyclic nucleotide-gated ion channel 4 (HCN4) current increases due to cAMP binding and is well-recognized to contribute to adrenergically driven heart rate acceleration. HCN4 current also increases with heat by an unknown mechanism(s). We use thermodynamical and homology computational modeling, site-directed mutagenesis, and mouse models to identify a concise motif on the S4-S5 linker of HCN4 channels (M407/Y409) that determines HCN4 current (If) responses to heat. This motif is required for heat-triggered rate acceleration in cardiac pacemaker cells, isolated hearts and in vivo. Surprisingly, a loss of function M407/Y409 motif mutation prevented not only normal heat but also cAMP responses, suggesting that the heat-sensing machinery within the S4-S5 linker is essential for operating the cAMP allosteric pathway and is central to HCN4 gating modulation. The M407/Y409 motif is conserved across all HCN family members suggesting that HCN channels participate broadly in coupling heat to changes in cell membrane excitability.

Suggested Citation

  • Yuejin Wu & Qinchuan Wang & Jonathan Granger & Oscar Reyes Gaido & Gabriel Lopez-Cecetaite & Eric Nunez Aguilar & Andreas Ludwig & Anna Moroni & Mario A. Bianchet & Mark E. Anderson, 2025. "HCN4 channels sense temperature and determine heart rate responses to heat," Nature Communications, Nature, vol. 16(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57358-9
    DOI: 10.1038/s41467-025-57358-9
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    References listed on IDEAS

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    1. Stefanie Fenske & Konstantin Hennis & René D. Rötzer & Verena F. Brox & Elvir Becirovic & Andreas Scharr & Christian Gruner & Tilman Ziegler & Verena Mehlfeld & Jaclyn Brennan & Igor R. Efimov & Audry, 2020. "cAMP-dependent regulation of HCN4 controls the tonic entrainment process in sinoatrial node pacemaker cells," Nature Communications, Nature, vol. 11(1), pages 1-22, December.
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