Article
- The EMBO Journal (2007) 26, 4423 - 4432
- doi:10.1038/sj.emboj.7601868
Published online: 4 October 2007
Subject Categories:
HCN4 provides a 'depolarization reserve' and is not required for heart rate acceleration in mice
Stefan Herrmann1,3, Juliane Stieber1,3, Georg Stöckl2, Franz Hofmann2 and Andreas Ludwig1
- Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
- Institut für Pharmakologie und Toxikologie, Technische Universität München, München, Germany
- These authors contributed equally to this work
Correspondence to:
Juliane Stieber, Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany. Tel.: +49 9131 85 26936; Fax: +49 9131 85 22774; E-mail: Stieber@pharmakologie.uni-erlangen.de
Andreas Ludwig, Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany. Tel.: +49 9131 85 22220; Fax: +49 9131 85 22774; E-mail: ludwig@pharmakologie.uni-erlangen.de
Received 30 March 2007; Accepted 5 September 2007
Abstract
Cardiac pacemaking involves a variety of ion channels, but their relative importance is controversial and remains to be determined. Hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels, which underlie the If current of sinoatrial cells, are thought to be key players in cardiac automaticity. In addition, the increase in heart rate following beta-adrenergic stimulation has been attributed to the cAMP-mediated enhancement of HCN channel activity. We have now studied mice in which the predominant sinoatrial HCN channel isoform HCN4 was deleted in a temporally controlled manner. Here, we show that deletion of HCN4 in adult mice eliminates most of sinoatrial If and results in a cardiac arrhythmia characterized by recurrent sinus pauses. However, the mutants show no impairment in heart rate acceleration during sympathetic stimulation. Our results reveal that unexpectedly the channel does not play a role for the increase of the heart rate; however, HCN4 is necessary for maintaining a stable cardiac rhythm, especially during the transition from stimulated to basal cardiac states.
Keywords:
- arrhythmia,
- HCN4,
- hyperpolarization-activated channels,
- pacemaking,
- sinoatrial node
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