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The mechanisms underlying heart automaticity are still poorly understood and controversial. Here we obtained, for the first time, complete conditional and time-controlled silencing of the hyperpolarization-activated "funny" current (If) by expression of a dominant-negative non-conductive human HCN4-channel subunit (hHCN4-AYA). Heart-specific If silencing recapitulated severe human disease of cardiac rhythm and conduction and showed that the functional role of f-channels in pacemaking critically depends on the activity of the autonomic nervous system. In line with this evidence, we were able to rescue 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 control. Our study establishes the role of f-channels in cardiac pacemaking and indicates that arrhythmia related to HCN loss-of-function in humans may be managed by pharmacological or genetic inhibition of GIRK4 channels, thus indicating a new unexplored therapeutic strategy to treat heart rhythm diseases. [ABSTRACT FROM AUTHOR]