TY  - JOUR
AU  - Harzheim, D.
AU  - Pfeiffer, K.H.
AU  - Fabritz, L.
AU  - Kremmer, E.
AU  - Buch, T.
AU  - Waisman, A.
AU  - Kirchhof, P.
AU  - Kaupp, U. B.
AU  - Seifert, R.
TI  - Cardiac pacemaker function of HCN4 channels in mice is confined to embryonic development and requires cyclic AMP
JO  - The EMBO journal online
VL  - 27
SN  - 0261-4189
CY  - London [u.a.]
PB  - Nature Publishing Group
M1  - PreJuSER-61425
SP  - 692 - 703
PY  - 2008
N1  - Record converted from VDB: 12.11.2012
AB  - 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.
KW  - Animals
KW  - Cells, Cultured
KW  - Cyclic AMP: physiology
KW  - Cyclic Nucleotide-Gated Cation Channels: genetics
KW  - Cyclic Nucleotide-Gated Cation Channels: physiology
KW  - Embryonic Development: physiology
KW  - Female
KW  - Heart: physiology
KW  - Heart Rate
KW  - Mice
KW  - Mice, Inbred C57BL
KW  - Mice, Transgenic
KW  - Mutation
KW  - Myocytes, Cardiac: physiology
KW  - Pregnancy
KW  - Cyclic Nucleotide-Gated Cation Channels (NLM Chemicals)
KW  - HCN3 protein, mouse (NLM Chemicals)
KW  - Cyclic AMP (NLM Chemicals)
KW  - J (WoSType)
LB  - PUB:(DE-HGF)16
C6  - pmid:18219271
C2  - pmc:PMC2262033
UR  - <Go to ISI:>//WOS:000253409300010
DO  - DOI:10.1038/emboj.2008.3
UR  - https://juser.fz-juelich.de/record/61425
ER  -