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Scientific article
Open access
English

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

Published inNature communications, vol. 5, 4664
Publication date2014-08-21
First online date2014-08-21
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.

eng
Keywords
  • Animals
  • Arrhythmias, Cardiac / drug therapy
  • Arrhythmias, Cardiac / genetics
  • Arrhythmias, Cardiac / physiopathology
  • Benzazepines / pharmacology
  • Calcium Signaling / genetics
  • Disease Models, Animal
  • Female
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels / genetics
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels / metabolism
  • Heart Rate / drug effects
  • Humans
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / genetics
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / metabolism
  • Ivabradine
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Muscle Proteins / genetics
  • Muscle Proteins / metabolism
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology
  • Oocytes / physiology
  • Patch-Clamp Techniques
  • Potassium Channels / genetics
  • Potassium Channels / metabolism
  • Pregnancy
  • Xenopus
Affiliation Not a UNIGE publication
Citation (ISO format)
MESIRCA, Pietro et al. Cardiac arrhythmia induced by genetic silencing of “funny” (f) channels is rescued by GIRK4 inactivation. In: Nature communications, 2014, vol. 5, p. 4664. doi: 10.1038/ncomms5664
Main files (1)
Article (Accepted version)
accessLevelPublic
Secondary files (10)
Identifiers
ISSN of the journal2041-1723
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17downloads

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