title: Cardiac arrhythmia induced by genetic silencing of 'funny' (f) channels is rescued by GIRK4 inactivation.
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.
authors.affiliation: 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.
authors.forename: Pietro
authors.initials: P
authors.lastname: Mesirca
authors.affiliation: Experimental Neuropediatrics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Alig
authors.affiliation: 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.
authors.forename: Angelo G
authors.initials: AG
authors.lastname: Torrente
authors.affiliation: Department of Cellular and Integrative Physiology, Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Jana Christina
authors.initials: JC
authors.lastname: Müller
authors.affiliation: 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.
authors.forename: Laurine
authors.initials: L
authors.lastname: Marger
authors.affiliation: 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.
authors.forename: Anne
authors.initials: A
authors.lastname: Rollin
authors.affiliation: 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.
authors.forename: Claire
authors.initials: C
authors.lastname: Marquilly
authors.affiliation: 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.
authors.forename: Anne
authors.initials: A
authors.lastname: Vincent
authors.affiliation: 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.
authors.forename: Stefan
authors.initials: S
authors.lastname: Dubel
authors.affiliation: 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.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Bidaud
authors.affiliation: Centre national de la recherche scientifique, UPR-1142, Institut de Génétique Humaine, F-34094 Montpellier, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Fernandez
authors.affiliation: 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.
authors.forename: Anika
authors.initials: A
authors.lastname: Seniuk
authors.affiliation: 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.
authors.forename: Birgit
authors.initials: B
authors.lastname: Engeland
authors.affiliation: Department of Experimental Pharmacology and Toxicology, Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Singh
authors.affiliation: Developmental Biology Institute of Marseille, Université Aix-Marseille, CNRS UMR 7288, 13288 Marseille, France.
authors.forename: Lucile
authors.initials: L
authors.lastname: Miquerol
authors.affiliation: 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.
authors.forename: Heimo
authors.initials: H
authors.lastname: Ehmke
authors.affiliation: 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.
authors.forename: Thomas
authors.initials: T
authors.lastname: Eschenhagen
authors.affiliation: 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.
authors.forename: Joel
authors.initials: J
authors.lastname: Nargeot
authors.affiliation: Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Wickman
authors.affiliation: 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].
authors.forename: Dirk
authors.initials: D
authors.lastname: Isbrandt
authors.affiliation: 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].
authors.forename: Matteo E
authors.initials: ME
authors.lastname: Mangoni
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology*; D001552:Benzazepines / Q000494:pharmacology; D020013:Calcium Signaling / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000235:genetics / Q000378:metabolism*; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000235:genetics* / Q000378:metabolism; D000077550:Ivabradine; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000235:genetics* / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D009865:Oocytes / Q000502:physiology; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000235:genetics* / Q000378:metabolism; D011247:Pregnancy; D014981:Xenopus
chemical_list: D001552:Benzazepines; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; C119587:HCN4 protein, human; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; C484273:Kcnj5 protein, mouse; D009124:Muscle Proteins; D015221:Potassium Channels; D000077550:Ivabradine