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Nat Commun. 2014 Aug 21;5:4664. doi: 10.1038/ncomms5664.

Cardiac arrhythmia induced by genetic silencing of 'funny' (f) channels is rescued by GIRK4 inactivation.

Author information

1
1] Département de Physiologie, Institut de Génomique Fonctionnelle, LabEx ICST, F-34094 Montpellier, France [2] UMR-5203, Centre national de la recherche scientifique, Universités de Montpellier 1 &2, F-34094 Montpellier, France [3] INSERM U661, Universités de Montpellier 1 &2, F-34094 Montpellier, France.
2
Experimental Neuropediatrics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
3
Department of Cellular and Integrative Physiology, Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
4
Centre national de la recherche scientifique, UPR-1142, Institut de Génétique Humaine, F-34094 Montpellier, France.
5
1] Department of Cellular and Integrative Physiology, Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany [2] Cardiovascular Research Center Hamburg (CVRC) and DZHK (German Center for Cardiovascular Research), University Medical Center Hamburg-Eppendorf, partner site Hamburg/Kiel/Luebeck, Martinistrasse 52, 20246 Hamburg, Germany.
6
1] Experimental Neuropediatrics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany [2] Experimental Neurophysiology, University Hospital Cologne, 50924 Cologne, Germany [3] German Center for Neurodegenerative Diseases (DZNE), 53175, Bonn, Germany.
7
Department of Experimental Pharmacology and Toxicology, Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
8
Developmental Biology Institute of Marseille, Université Aix-Marseille, CNRS UMR 7288, 13288 Marseille, France.
9
1] Cardiovascular Research Center Hamburg (CVRC) and DZHK (German Center for Cardiovascular Research), University Medical Center Hamburg-Eppendorf, partner site Hamburg/Kiel/Luebeck, Martinistrasse 52, 20246 Hamburg, Germany [2] Department of Experimental Pharmacology and Toxicology, Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
10
Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota 55455, USA.
11
1] Experimental Neuropediatrics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany [2] Experimental Neurophysiology, University Hospital Cologne, 50924 Cologne, Germany [3] German Center for Neurodegenerative Diseases (DZNE), 53175, Bonn, Germany [4].
12
1] Département de Physiologie, Institut de Génomique Fonctionnelle, LabEx ICST, F-34094 Montpellier, France [2] UMR-5203, Centre national de la recherche scientifique, Universités de Montpellier 1 &2, F-34094 Montpellier, France [3] INSERM U661, Universités de Montpellier 1 &2, F-34094 Montpellier, France [4].

Abstract

The mechanisms underlying cardiac automaticity are still incompletely understood and controversial. Here we report the complete conditional and time-controlled silencing of the 'funny' current (If) by expression of a dominant-negative, non-conductive HCN4-channel subunit (hHCN4-AYA). Heart-specific If silencing caused altered [Ca(2+)]i release and Ca(2+) handling in the sinoatrial node, impaired pacemaker activity and symptoms reminiscent of severe human disease of pacemaking. The effects of If silencing critically depended on the activity of the autonomic nervous system. We were able to rescue the failure of impulse generation and conduction by additional genetic deletion of cardiac muscarinic G-protein-activated (GIRK4) channels in If-deficient mice without impairing heartbeat regulation. Our study establishes the role of f-channels in cardiac automaticity and indicates that arrhythmia related to HCN loss-of-function may be managed by pharmacological or genetic inhibition of GIRK4 channels, thus offering a new therapeutic strategy for the treatment of heart rhythm diseases.

PMID:
25144323
PMCID:
PMC4207211
DOI:
10.1038/ncomms5664
[Indexed for MEDLINE]
Free PMC Article

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