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@ARTICLE{Harzheim:61425,
author = {Harzheim, D. and Pfeiffer, K.H. and Fabritz, L. and
Kremmer, E. and Buch, T. and Waisman, A. and Kirchhof, P.
and Kaupp, U. B. and Seifert, R.},
title = {{C}ardiac pacemaker function of {HCN}4 channels in mice is
confined to embryonic development and requires cyclic {AMP}},
journal = {The EMBO journal online},
volume = {27},
issn = {0261-4189},
address = {London [u.a.]},
publisher = {Nature Publishing Group},
reportid = {PreJuSER-61425},
pages = {692 - 703},
year = {2008},
note = {Record converted from VDB: 12.11.2012},
abstract = {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.},
keywords = {Animals / Cells, Cultured / Cyclic AMP: physiology / Cyclic
Nucleotide-Gated Cation Channels: genetics / Cyclic
Nucleotide-Gated Cation Channels: physiology / Embryonic
Development: physiology / Female / Heart: physiology / Heart
Rate / Mice / Mice, Inbred C57BL / Mice, Transgenic /
Mutation / Myocytes, Cardiac: physiology / Pregnancy /
Cyclic Nucleotide-Gated Cation Channels (NLM Chemicals) /
HCN3 protein, mouse (NLM Chemicals) / Cyclic AMP (NLM
Chemicals) / J (WoSType)},
cin = {INB-1},
ddc = {570},
cid = {I:(DE-Juel1)VDB804},
pnm = {Funktion und Dysfunktion des Nervensystems},
pid = {G:(DE-Juel1)FUEK409},
shelfmark = {Biochemistry $\&$ Molecular Biology / Cell Biology},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:18219271},
pmc = {pmc:PMC2262033},
UT = {WOS:000253409300010},
doi = {10.1038/emboj.2008.3},
url = {https://juser.fz-juelich.de/record/61425},
}