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

EMBO J. 2007 Oct 31;26(21):4423-32. doi: 10.1038/sj.emboj.7601868. Epub 2007 Oct 4.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cyclic AMP / metabolism
  • Cyclic Nucleotide-Gated Cation Channels / metabolism*
  • Gene Expression Regulation*
  • Heart Rate*
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
  • Ion Channel Gating
  • Ion Channels / metabolism
  • Isoproterenol / pharmacology
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Mutation
  • Protein Isoforms
  • Sinoatrial Node / metabolism
  • Sinoatrial Node / pathology


  • Cyclic Nucleotide-Gated Cation Channels
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
  • Ion Channels
  • Protein Isoforms
  • Cyclic AMP
  • Isoproterenol