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

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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.