The hyperpolarization-activated channel HCN4 is required for the generation of pacemaker action potentials in the embryonic heart
The hyperpolarization-activated channel HCN4 is required for the generation of pacemaker action potentials in the embryonic heart
复制标题
DOI：
10.1073/pnas.2434235100
复制
发表时间：
2003-12-09
影响因子：
11.1
通讯作者：
Ludwig, A
中科院分区：
文献类型：
--
作者：
Stieber, J;Herrmann, S;Ludwig, A
超极化激活的环核苷酸门控阳离子电流，称为I-f或I-h，由超极化激活的环核苷酸门控阳离子（HCN）通道家族的四个成员产生。这些电流已经被提出有助于几种功能，包括心脏和大脑中的起搏器活动，静息电位的控制和神经元可塑性。在心肌细胞和神经元中发现了HCN 4亚型的转录本，但该通道的生理作用尚不清楚。在这里，我们表明，HCN 4是必不可少的发展心脏传导系统的正常功能。在野生型胚胎中，HCN 4在早期窦房结发育的心脏区域高度表达。缺乏HCN 4通道的小鼠，以及心肌细胞中HCN 4选择性缺失的小鼠，在胚胎第9.5和11.5天之间死亡。平均而言，突变胚胎心肌细胞中的If减少了85%。与野生型相比，HCN 4缺陷型胚胎的心脏收缩明显较慢，并且不能被cAMP刺激。在野生型和HCN 4（-/-）小鼠中，都能发现具有“原始”起搏动作电位的心肌细胞，而在HCN 4缺陷型小鼠胚胎中则没有发现具有“成熟”起搏动作电位的心肌细胞。因此，HCN 4通道对于在新生窦房结中正确产生起搏电位是必不可少的。
Hyperpolarization-activated, cyclic nucleotide-gated cation currents, termed I-f or I-h, are generated by four members of the hyperpolarization-activated, cyclic nucleotide-gated cation (HCN) channel family. These currents have been proposed to contribute to several functions including pacemaker activity in heart and brain, control of resting potential, and neuronal plasticity. Transcripts of the HCN4 isoform have been found in cardiomyocytes and neurons, but the physiological role of this channel is unknown. Here we show that HCN4 is essential for the proper function of the developing cardiac conduction system. In wild-type embryos, HCN4 is highly expressed in the cardiac region where the early sinoatrial node develops. Mice lacking HCN4 channels globally, as well as mice with a selective deletion of HCN4 in cardiomyocytes, died between embryonic days 9.5 and 11.5. On average, If in cardiomyocytes from mutant embryos is reduced by 85%. Hearts from HCN4-deficient embryos contracted significantly slower compared with wild type and could not be stimulated by cAMP. In both wild-type and HCN4(-/-) mice, cardiac cells with "primitive" pacemaker action potentials could be found. However, cardiac cells with "mature" pacemaker potentials, observed in wild-type embryos starting at day 9.0, were not detected in HCN4-deficient embryos. Thus, HCN4 channels are essential for the proper generation of pacemaker potentials in the emerging sinoatrial node.