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 () and Christian Wahl-Schott ()
Additional contact information
Stefanie Fenske: Ludwig-Maximilians-Universität München
Konstantin Hennis: Ludwig-Maximilians-Universität München
René D. Rötzer: Ludwig-Maximilians-Universität München
Verena F. Brox: Ludwig-Maximilians-Universität München
Elvir Becirovic: Ludwig-Maximilians-Universität München
Andreas Scharr: Ludwig-Maximilians-Universität München
Christian Gruner: Ludwig-Maximilians-Universität München
Tilman Ziegler: Partner Site Munich Heart Alliance
Verena Mehlfeld: Ludwig-Maximilians-Universität München
Jaclyn Brennan: George Washington University
Igor R. Efimov: George Washington University
Audrys G. Pauža: Lithuanian University of Health Sciences, LT
Markus Moser: Max Planck Institute of Biochemistry, Department of Molecular Medicine
Carsten T. Wotjak: Research Group Neuronal Plasticity
Christian Kupatt: Partner Site Munich Heart Alliance
Rasmus Gönner: Ludwig-Maximilians-Universität München
Rai Zhang: University of Bristol
Henggui Zhang: The University of Manchester
Xiangang Zong: Ludwig-Maximilians-Universität München
Martin Biel: Ludwig-Maximilians-Universität München
Christian Wahl-Schott: Institute for Neurophysiology

Nature Communications, 2020, vol. 11, issue 1, 1-22

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-19304-9

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