cAMP-dependent regulation of HCN4 controls the tonic entrainment process in sinoatrial node pacemaker cells

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, Audrys G. Pauža, Markus Moser, Carsten T. Wotjak, Christian Kupatt, Rasmus Gönner, Rai Zhang, Henggui Zhang, Xiangang Zong, Martin Biel*Christian Wahl-Schott

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

46 Scopus citations


It is highly debated how cyclic adenosine monophosphate-dependent regulation (CDR) of the major pacemaker channel HCN4 in the sinoatrial node (SAN) is involved in heart rate regulation by the autonomic nervous system. We addressed this question using a knockin mouse line expressing cyclic adenosine monophosphate-insensitive HCN4 channels. This mouse line displayed a complex cardiac phenotype characterized by sinus dysrhythmia, severe sinus bradycardia, sinus pauses and chronotropic incompetence. Furthermore, the absence of CDR leads to inappropriately enhanced heart rate responses of the SAN to vagal nerve activity in vivo. The mechanism underlying these symptoms can be explained by the presence of nonfiring pacemaker cells. We provide evidence that a tonic and mutual interaction process (tonic entrainment) between firing and nonfiring cells slows down the overall rhythm of the SAN. Most importantly, we show that the proportion of firing cells can be increased by CDR of HCN4 to efficiently oppose enhanced responses to vagal activity. In conclusion, we provide evidence for a novel role of CDR of HCN4 for the central pacemaker process in the sinoatrial node.

Original languageEnglish (US)
Article number5555
JournalNature communications
Issue number1
StatePublished - Dec 1 2020

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)


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