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  Cardiac pacemaker function of HCN4 channels in mice is confined to embryonic development and requires cyclic AMP

Harzheim, D., Pfeiffer, K. H., Fabritz, L., Kremmer, E., Buch, T., Waisman, A., et al. (2008). Cardiac pacemaker function of HCN4 channels in mice is confined to embryonic development and requires cyclic AMP. EMBO Journal, 27(4), 692-703.

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Item Permalink: https://hdl.handle.net/11858/00-001M-0000-0028-6491-8 Version Permalink: https://hdl.handle.net/11858/00-001M-0000-0028-6492-6
Genre: Journal Article

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Harzheim, D.1, Author
Pfeiffer, K. H., Author
Fabritz, L., Author
Kremmer, E., Author
Buch, T., Author
Waisman, A., Author
Kirchhof, P., Author
Kaupp, U. B.1, Author
Seifert, R.1, Author
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1External Organizations, ou_persistent22              

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 Abstract: 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

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 Dates: 2008
 Publication Status: Issued
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 Identifiers: ISI: ISI:000253409300010
ISSN: 0261-4189
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Title: EMBO Journal
  Alternative Title : EMBO J.
Source Genre: Journal
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Pages: - Volume / Issue: 27 (4) Sequence Number: - Start / End Page: 692 - 703 Identifier: -