Cardiac pacemaker function of HCN4 channels in mice is confined to embryonic development and requires cyclic AMP.
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.
Harzheim
Dagmar
D
Forschungszentrum Jülich, Institut für Neurowissenschaften und Biophysik, Abteilung Zelluläre Biophysik, Jülich, Germany.
Pfeiffer
K Holger
KH
Fabritz
Larissa
L
Kremmer
Elisabeth
E
Buch
Thorsten
T
Waisman
Ari
A
Kirchhof
Paulus
P
Kaupp
U Benjamin
UB
Seifert
Reinhard
R
D000818:Animals; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000502:physiology*; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000235:genetics / Q000502:physiology*; D047108:Embryonic Development / Q000502:physiology*; D005260:Female; D006321:Heart / Q000502:physiology*; D006339:Heart Rate; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D032383:Myocytes, Cardiac / Q000502:physiology; D011247:Pregnancy
D054815:Cyclic Nucleotide-Gated Cation Channels; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D000242:Cyclic AMP