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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Bibliographic Details
Published in:Nature communications Vol. 5; no. 1; p. 4664
Main Authors: 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
Language:English
Published: London Nature Publishing Group UK 21.08.2014
Nature Publishing Group
Subjects:
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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
Online Access:Get full text
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Summary: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.
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PMCID: PMC4207211
Dirk Isbrandt and Matteo E. Mangoni are joint senior authors
ISSN:2041-1723
2041-1723
DOI:10.1038/ncomms5664