HCN4 provides a 'depolarization reserve' and is not required for heart rate acceleration in mice
HCN4 provides a 'depolarization reserve' and is not required for heart rate acceleration in mice
复制标题
DOI：
10.1038/sj.emboj.7601868
复制
发表时间：
2007-10-31
期刊：
影响因子：
11.4
通讯作者：
Ludwig, Andreas
中科院分区：
文献类型：
--
作者：
Herrmann, Stefan;Stieber, Juliane;Ludwig, Andreas
心脏起搏涉及多种离子通道，但它们的相对重要性是有争议的，仍有待确定。超极化激活的环核苷酸门控（HCN）通道是窦房细胞If电流的基础，被认为是心脏自律性的关键参与者。此外，β-肾上腺素能刺激后心率的增加归因于cAMP介导的HCN通道活性的增强。我们现在已经研究了小鼠，其中占主导地位的窦房HCN通道亚型HCN 4被删除在一个时间控制的方式。在这里，我们表明，在成年小鼠中的HCN 4删除消除了大部分的窦房如果和结果的心律失常的特点是反复窦性停搏。然而，突变体在交感神经刺激期间没有显示心率加速的损害。我们的研究结果表明，出乎意料的是，该通道并没有发挥作用的心率的增加，但是，HCN 4是必要的，以维持一个稳定的心律，特别是在从刺激到基础的心脏状态的过渡。
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.