ArticleNature communications2014
Cardiac arrhythmia induced by genetic silencing of 'funny' (f) channels is rescued by GIRK4 inactivation.
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Article in Nature communications, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers.
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47 citing papers in PubMed, 81 citations in OpenAlex.
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- The funny current If is essential for the fight-or-flight response in cardiac pacemaker cells.The Journal of general physiology · 2022Article
- Paradigm shift: new concepts for HCN4 function in cardiac pacemaking.Pflugers Archiv : European journal of physiology · 2022Review
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- Characterization of VU0468554, a New Selective Inhibitor of Cardiac G Protein-Gated Inwardly Rectifying KMolecular pharmacology · 2021Article
- ESC working group on cardiac cellular electrophysiology position paper: relevance, opportunities, and limitations of experimental models for cardiac electrophysiology research.Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology · 2021Review
- Developmental HCN channelopathy results in decreased neural progenitor proliferation and microcephaly in mice.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Pharmacologic Approach to Sinoatrial Node Dysfunction.Annual review of pharmacology and toxicology · 2021Review
- Speeding Up the Heart? Traditional and New Perspectives on HCN4 Function.Frontiers in physiology · 2021Review
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Authors and funding
21 authors at 9 institutions in 3 countries.
Pietro Mesirca1] 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.
Jacqueline AligExperimental Neuropediatrics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
Angelo G Torrente1] 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.
Jana Christina MüllerDepartment of Cellular and Integrative Physiology, Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
Laurine Marger1] 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.
Anne Rollin1] 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.
Claire Marquilly1] 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.
Anne Vincent1] 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.
Stefan Dubel1] 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.
Isabelle Bidaud1] 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.
Anne FernandezCentre national de la recherche scientifique, UPR-1142, Institut de Génétique Humaine, F-34094 Montpellier, France.
Anika Seniuk1] 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.
Birgit Engeland1] 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.
Jasmin SinghDepartment of Experimental Pharmacology and Toxicology, Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
Lucile MiquerolDevelopmental Biology Institute of Marseille, Université Aix-Marseille, CNRS UMR 7288, 13288 Marseille, France.
Heimo Ehmke1] 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.
Thomas Eschenhagen1] 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.
Joel Nargeot1] 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.
Kevin WickmanDepartment of Pharmacology, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Dirk Isbrandt1] 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].
Matteo E Mangoni1] 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].
Université de Montpellier · FRUniversity Medical Center Hamburg-Eppendorf · DEInstitut de Génomique Fonctionnelle · FRLaboratoire d'Excellence Canaux Ioniques d'Intérêt Thérapeutique · FRUniversität Hamburg · DECentre National de la Recherche Scientifique · FRGerman Centre for Cardiovascular Research · DEInstitut de Génétique Humaine · FRUniversity of Minnesota · US
Funding
The role of RGS proteins in the parasympathetic control of heart rateR01HL105550 · NHLBI · UNIVERSITY OF MINNESOTA · PI MARTEMYANOV, KIRILL A., WICKMAN, KEVIN D · 2011 to 2018
$3.2MModulation of Cav 1.3 L-type Ca2+ channels by PDZ-protein interactionsR01HL087120 · NHLBI · UNIVERSITY OF IOWA · PI LEE, AMY · 2009 to 2012
$1.4MNHLBI NIH HHS R01 HL087120NHLBI NIH HHS R01HL087120-A2NHLBI NIH HHS R01 HL105550NHLBI NIH HHS R01HL105550
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.
Indexed as
AnimalsArrhythmias, CardiacBenzazepinesCalcium SignalingDisease Models, AnimalFemaleG Protein-Coupled Inwardly-Rectifying Potassium ChannelsHeart RateHumansHyperpolarization-Activated Cyclic Nucleotide-Gated ChannelsIvabradineMaleMiceMice, Inbred C57BLMice, TransgenicMuscle ProteinsBenzazepinesG Protein-Coupled Inwardly-Rectifying Potassium ChannelsHCN4 protein, humanHyperpolarization-Activated Cyclic Nucleotide-Gated ChannelsIvabradineKcnj5 protein, mouseMuscle ProteinsPotassium Channels
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