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

Pietro Mesirca, Jacqueline Alig, Angelo G. Torrente, Jana Christina Müller, Laurine Marger, Anne Rollin, Claire Marquilly, Anne Vincent, Stefan Dubel, Isabelle Bidaud, Anne Fernandez, Anika Seniuk, Birgit Engeland, Jasmin Singh, Lucile Miquerol, Heimo Ehmke, Thomas Eschenhagen, Joel Nargeot, Kevin Wickman, Dirk Isbrandt and Matteo E. Mangoni ()
Additional contact information
Pietro Mesirca: Institut de Génomique Fonctionnelle, LabEx ICST
Jacqueline Alig: Experimental Neuropediatrics, University Medical Center Hamburg-Eppendorf
Angelo G. Torrente: Institut de Génomique Fonctionnelle, LabEx ICST
Jana Christina Müller: Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf
Laurine Marger: Institut de Génomique Fonctionnelle, LabEx ICST
Anne Rollin: Institut de Génomique Fonctionnelle, LabEx ICST
Claire Marquilly: Institut de Génomique Fonctionnelle, LabEx ICST
Anne Vincent: Institut de Génomique Fonctionnelle, LabEx ICST
Stefan Dubel: Institut de Génomique Fonctionnelle, LabEx ICST
Isabelle Bidaud: Institut de Génomique Fonctionnelle, LabEx ICST
Anne Fernandez: Centre national de la recherche scientifique, UPR-1142, Institut de Génétique Humaine
Anika Seniuk: Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf
Birgit Engeland: Experimental Neuropediatrics, University Medical Center Hamburg-Eppendorf
Jasmin Singh: Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf
Lucile Miquerol: Developmental Biology Institute of Marseille, Université Aix-Marseille, CNRS UMR 7288
Heimo Ehmke: Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf
Thomas Eschenhagen: Cardiovascular Research Center Hamburg (CVRC) and DZHK (German Center for Cardiovascular Research), University Medical Center Hamburg-Eppendorf
Joel Nargeot: Institut de Génomique Fonctionnelle, LabEx ICST
Kevin Wickman: University of Minnesota
Dirk Isbrandt: Experimental Neuropediatrics, University Medical Center Hamburg-Eppendorf
Matteo E. Mangoni: Institut de Génomique Fonctionnelle, LabEx ICST

Nature Communications, 2014, vol. 5, issue 1, 1-15

Abstract: 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 [Ca2+]i release and Ca2+ 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.

Date: 2014
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DOI: 10.1038/ncomms5664

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