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- W2014303946 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. The ‘funny’ current (If) is important for the generation and regulation of the heart’s automaticity. Here the authors show that If silencing through genetic modification of the f-channel component HCN4 causes heart arrhythmia by altering Ca2+handling in pacemaker myocytes." @default.
- W2014303946 created "2016-06-24" @default.
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- W2014303946 date "2014-08-21" @default.
- W2014303946 modified "2023-10-16" @default.
- W2014303946 title "Cardiac arrhythmia induced by genetic silencing of ‘funny’ (f) channels is rescued by GIRK4 inactivation" @default.
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- W2014303946 doi "https://doi.org/10.1038/ncomms5664" @default.
- W2014303946 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/4207211" @default.
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