Cardiac pacemaker function of HCN4 channels in mice is confined to embryonic development and requires cyclic AMP
Cardiac pacemaker function of HCN4 channels in mice is confined to embryonic development and requires cyclic AMP
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DOI：
10.1038/emboj.2008.3
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发表时间：
2008-02-20
期刊：
影响因子：
11.4
通讯作者：
Seifert, Reinhard
中科院分区：
文献类型：
--
作者：
Harzheim, Dagmar;Pfeiffer, K. Holger;Seifert, Reinhard
心脏中cAMP信号传导的重要靶点是超极化激活和环核苷酸门控（HCN）通道，它们是去极化“起搏器”电流If的基础。我们研究了If在小鼠中的作用，其中cAMP与HCN 4通道的结合被单个氨基酸交换（R669 Q）废除。纯合子HCN 4（R669 Q/R669 Q）小鼠在胚胎发育期间死亡。在E12之前，纯合子和杂合子胚胎显示心率降低，对儿茶酚胺刺激没有反应或反应减弱。成年杂合子小鼠在休息和运动时心率正常。然而，在β-肾上腺素能刺激后，心脏表现出停顿和窦房结阻滞。我们的研究结果表明，在胚胎中，HCN 4是一个真正的心脏起搏器和升高的HCN 4通道活性的cAMP是必不可少的生存能力。在成年小鼠中，HCN 4通道的一个重要功能是防止应激期间和应激后的窦性停搏，而它们作为小鼠心脏起搏器的作用受到质疑。最重要的是，我们的研究结果表明，HCN 4通道可以履行其生理功能，只有当cAMP的约束。
Important targets for cAMP signalling in the heart are hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels that underlie the depolarizing 'pacemaker' current, If. We studied the role of If in mice, in which binding of cAMP to HCN4 channels was abolished by a single amino-acid exchange (R669Q). Homozygous HCN4(R669Q/R669Q) mice die during embryonic development. Prior to E12, homozygous and heterozygous embryos display reduced heart rates and show no or attenuated responses to catecholaminergic stimulation. Adult heterozygous mice display normal heart rates at rest and during exercise. However, following beta-adrenergic stimulation, hearts exhibit pauses and sino-atrial node block. Our results demonstrate that in the embryo, HCN4 is a true cardiac pacemaker and elevation of HCN4 channel activity by cAMP is essential for viability. In adult mice, an important function of HCN4 channels is to prevent sinus pauses during and after stress while their role as a pacemaker of the murine heart is put into question. Most importantly, our results indicate that HCN4 channels can fulfil their physiological function only when cAMP is bound.