HCN4 channels sense temperature and determine heart rate responses to heat

Wu Y, Wang Q, Granger J, Reyes Gaido O, Lopez-Cecetaite G, Aguilar EN, Ludwig A, Moroni A, Bianchet MA, Anderson ME (2025)

Publication Type: Journal article

Publication year: 2025

Journal

Nature Communications Nature Publishing Group: Nature Communications

Book Volume: 16

Article Number: 2102

Journal Issue: 1

DOI: 10.1038/s41467-025-57358-9

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.

Authors with CRIS profile

Andreas Ludwig Lehrstuhl für Pharmakologie und Toxikologie

Additional Organisation(s)

FAU Forschungszentrum Neue Wirkstoffe (FAU NeW)

Involved external institutions

Università degli studi di Milano IT Italy (IT) Johns Hopkins Hospital US United States (USA) (US)

How to cite

APA:

Wu, Y., Wang, Q., Granger, J., Reyes Gaido, O., Lopez-Cecetaite, G., Aguilar, E.N.,... Anderson, M.E. (2025). HCN4 channels sense temperature and determine heart rate responses to heat. Nature Communications, 16(1). https://doi.org/10.1038/s41467-025-57358-9

MLA:

Wu, Yuejin, et al. "HCN4 channels sense temperature and determine heart rate responses to heat." Nature Communications 16.1 (2025).

BibTeX: Download