Harzheim Dagmar, Pfeiffer K Holger, Fabritz Larissa, Kremmer Elisabeth, Buch Thorsten, Waisman Ari, Kirchhof Paulus, Kaupp U Benjamin, Seifert Reinhard
Forschungszentrum Jülich, Institut für Neurowissenschaften und Biophysik, Abteilung Zelluläre Biophysik, Jülich, Germany.
EMBO J. 2008 Feb 20;27(4):692-703. doi: 10.1038/emboj.2008.3. Epub 2008 Jan 24.
Important targets for cAMP signalling in the heart are hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels that underlie the depolarizing 'pacemaker' current, I(f). We studied the role of I(f) 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.
环磷酸腺苷（cAMP）信号传导在心脏中的重要靶点是超极化激活的环核苷酸门控（HCN）通道，该通道是去极化“起搏”电流I(f)的基础。我们研究了I(f)在小鼠中的作用，在这些小鼠中，通过单个氨基酸交换（R669Q）消除了cAMP与HCN4通道的结合。纯合子HCN4(R669Q/R669Q)小鼠在胚胎发育期间死亡。在胚胎第12天之前，纯合子和杂合子胚胎的心率降低，并且对儿茶酚胺能刺激无反应或反应减弱。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，心脏出现停顿和窦房结阻滞。我们的结果表明，在胚胎中，HCN4是真正的心脏起搏器，cAMP升高HCN4通道活性对生存能力至关重要。在成年小鼠中，HCN4通道的一个重要功能是在应激期间和之后防止窦性停顿，而其作为小鼠心脏起搏器的作用受到质疑。最重要的是，我们的结果表明，HCN4通道只有在结合cAMP时才能发挥其生理功能。
