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| Subject Categories: Development | Molecular Biology of Disease |
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| The EMBO Journal
(2008) 27, 692–703, doi:10.1038/emboj.2008.3 Published online 24 January 2008 |
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| Cardiac pacemaker function of HCN4 channels in mice is confined to embryonic development and requires cyclic AMP |
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| Dagmar Harzheim1, 6, K Holger Pfeiffer1, Larissa Fabritz2, Elisabeth Kremmer3, Thorsten Buch4, Ari Waisman5, Paulus Kirchhof2, U Benjamin Kaupp1, 7 and Reinhard Seifert1 |
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1 Forschungszentrum Jülich, Institut für Neurowissenschaften und Biophysik, Abteilung Zelluläre Biophysik, Jülich, Germany 2 Medizinische Klinik und Poliklinik C, Universitätsklinikum Münster und IZKF Münster, Münster, Germany 3 GSF, Institut für Molekulare Immunologie, München, Germany 4 Institut für Experimentelle Immunologie, Universität Zürich, Zürich, Switzerland 5 I Medizinische und Poliklinik, Johannes Gutenberg-Universität Mainz, Mainz, Germany 6 Present address: Laboratory of Molecular Signalling, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK 7 Present address: Stiftung Caesar, Ludwig-Erhard-Allee 2, 53175 Bonn To whom correspondence should be addressed U Benjamin Kaupp, Institut fuer Neurowissenschaften, Forschungszentrum Juelich, INB-1, Jülich 52425, Germany. Tel.: +49 2461 6140 41; Fax: +49 2461 6142 16; E-mail: a.eckert@fz-juelich.de Reinhard Seifert, Institut fuer Neurowissenschaften, Forschungszentrum Juelich, INB-1, Jülich 52425, Germany. Tel.: +49 2461 6140 41; Fax: +49 2461 6142 16; E-mail: r.seifert@fz-juelich.de Received 22 March 2007; Accepted 21 December 2007; Published online 24 January 2008. |
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| Abstract |
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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 HCN4R669Q/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  -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. |
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| Keywords: cardiology, cyclic nucleotides, heart, ion channel, signalling |
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Top of page MORE ARTICLES LIKE THISThese links to content published by NPG are automatically generated NEWS AND VIEWSPresynaptic facilitation by hyperpolarization-activated pacemaker channels Nature Neuroscience News and Views (01 Feb 2000) Nature Medicine News and Views (01 Dec 2005) |
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