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.
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