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

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 ( I f ) by expression of a dominant-negative, non-conductive HCN4-channel subunit (hHCN4-AYA). Heart-specif...

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Veröffentlicht in:	Nature communications Jg. 5; H. 1; S. 4664
Hauptverfasser:	Mesirca, Pietro, Alig, Jacqueline, Torrente, Angelo G., Müller, Jana Christina, Marger, Laurine, Rollin, Anne, Marquilly, Claire, Vincent, Anne, Dubel, Stefan, Bidaud, Isabelle, Fernandez, Anne, Seniuk, Anika, Engeland, Birgit, Singh, Jasmin, Miquerol, Lucile, Ehmke, Heimo, Eschenhagen, Thomas, Nargeot, Joel, Wickman, Kevin, Isbrandt, Dirk, Mangoni, Matteo E.
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	London Nature Publishing Group UK 21.08.2014 Nature Publishing Group
Schlagworte:	14/32 14/34 42/41 631/208/2489/144 631/208/2489/201 631/443/592/75/29 9/74 Animals Arrhythmias, Cardiac - drug therapy Arrhythmias, Cardiac - genetics Arrhythmias, Cardiac - physiopathology Benzazepines - pharmacology Calcium Signaling - genetics Cardiology and cardiovascular system Disease Models, Animal Female G Protein-Coupled Inwardly-Rectifying Potassium Channels - genetics G Protein-Coupled Inwardly-Rectifying Potassium Channels - metabolism Genetics Heart Rate - drug effects Human health and pathology Humanities and Social Sciences Humans Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels - genetics Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels - metabolism Inactivation Life Sciences Male Mice Mice, Inbred C57BL Mice, Transgenic multidisciplinary Muscle Proteins - genetics Muscle Proteins - metabolism Myocytes, Cardiac - metabolism Myocytes, Cardiac - pathology Oocytes - physiology Patch-Clamp Techniques Potassium Channels - genetics Potassium Channels - metabolism Pregnancy Science Science (multidisciplinary) Xenopus Gene therapy Arrhythmias Disease genetics
ISSN:	2041-1723, 2041-1723
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Zusammenfassung:	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 ( I f ) by expression of a dominant-negative, non-conductive HCN4-channel subunit (hHCN4-AYA). Heart-specific I f 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 I f 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 I f -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. The ‘funny’ current ( I f ) is important for the generation and regulation of the heart’s automaticity. Here the authors show that I f silencing through genetic modification of the f -channel component HCN4 causes heart arrhythmia by altering Ca 2+ handling in pacemaker myocytes.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 content type line 14 ObjectType-Feature-2 content type line 23 PMCID: PMC4207211 Dirk Isbrandt and Matteo E. Mangoni are joint senior authors
ISSN:	2041-1723 2041-1723
DOI:	10.1038/ncomms5664