HCN4 channels sense temperature and determine heart rate responses to heat

Yuejin Wu (), Qinchuan Wang, Jonathan Granger, Oscar Reyes Gaido, Gabriel Lopez-Cecetaite, Eric Nunez Aguilar, Andreas Ludwig, Anna Moroni, Mario A. Bianchet and Mark E. Anderson ()
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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

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-57358-9

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