HCN4 provides a 'depolarization reserve' and is not required for heart rate acceleration in mice |
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Authors: | Herrmann Stefan Stieber Juliane Stöckl Georg Hofmann Franz Ludwig Andreas |
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Institution: | 1.Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany;2.Institut für Pharmakologie und Toxikologie, Technische Universität München, München, Germany;3.These authors contributed equally to this work |
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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 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. |
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Keywords: | arrhythmia HCN4 hyperpolarization-activated channels pacemaking sinoatrial node |
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