HCN4 channels sense temperature and determine heart rate responses to heat
Yuejin Wu, Qinchuan Wang, Jonathan Granger, Oscar E. Reyes Gaido, Gabriel Lopez-Cecetaite, Eric N. Aguilar, A. Ludwig, Anna Moroni, Mario A. Bianchet, Mark E. Anderson
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. Heat increases heart rate across vertebrates. Here, authors pinpoint a motif in the HCN4 channel that governs heat-driven heart rate acceleration and demonstrate its conserved role in other HCN channels, revealing a conserved mechanism linking temperature to membrane excitability.