XB-ART-53261
Nat Commun
2014 Aug 21;5:4664. doi: 10.1038/ncomms5664.
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Cardiac arrhythmia induced by genetic silencing of 'funny' (f) channels is rescued by GIRK4 inactivation.
Mesirca P
,
Alig J
,
Torrente AG
,
Müller JC
,
Marger L
,
Rollin A
,
Marquilly C
,
Vincent A
,
Dubel S
,
Bidaud I
,
Fernandez A
,
Seniuk A
,
Engeland B
,
Singh J
,
Miquerol L
,
Ehmke H
,
Eschenhagen T
,
Nargeot J
,
Wickman K
,
Isbrandt D
,
Mangoni ME
.
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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.
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R01 HL087120 NHLBI NIH HHS , R01 HL105550 NHLBI NIH HHS , R01HL087120-A2 NHLBI NIH HHS , R01HL105550 NHLBI NIH HHS
Species referenced: Xenopus
Genes referenced: hcn1 hcn4 kcnj5 naa50 nodal
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