HCN4 provides a 'depolarization reserve' and is not required for heart rate acceleration in mice

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 I f current of sinoatrial cells, are thought to be key players in cardiac automa...

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Bibliographic Details
Published in:The EMBO journal 2007-10, Vol.26 (21), p.4423-4432
Main Authors: Herrmann, Stefan, Stieber, Juliane, Stöckl, Georg, Hofmann, Franz, Ludwig, Andreas
Format: Article
Language:English
Subjects:
Animals
arrhythmia
Biochemistry
Biomedical research
Cardiac arrhythmia
Cardiovascular system
Cellular biology
Cyclic AMP - metabolism
Cyclic Nucleotide-Gated Cation Channels - metabolism
Gene Expression Regulation
HCN4
Heart Rate
hyperpolarization-activated channels
Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
Ion Channel Gating
Ion Channels - metabolism
Isoproterenol - pharmacology
Mice
Mice, Knockout
Mice, Transgenic
Mutation
pacemaking
Protein Isoforms
Rodents
sinoatrial node
Sinoatrial Node - metabolism
Sinoatrial Node - pathology
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Summary: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 I f 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 I f 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.
ISSN:0261-4189
1460-2075
DOI:10.1038/sj.emboj.7601868