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Cardiac glycosides have been used in the treatment of arrhythmias for more than 200 years. Two-pore-domain (K 2P ) potassium channels regulate cardiac action potential repolarization. Recently, K 2P 3.1 [tandem of P domains in a weak inward rectifying K + channel (TWIK)-related acid-sensitive K + channel (TASK)-1] has been implicated in atrial fibrillation pathophysiology and was suggested as an atrial-selective antiarrhythmic drug target. We hypothesized that blockade of cardiac K 2P channels contributes to the mechanism of action of digitoxin and digoxin. All functional human K 2P channels were screened for interactions with cardiac glycosides. Human K 2P channel subunits were expressed in Xenopus laevis oocytes, and voltage clamp electrophysiology was used to record K + currents. Digitoxin significantly inhibited K 2P 3.1 and K 2P 16.1 channels. By contrast, digoxin displayed isolated inhibitory effects on K 2P 3.1. K 2P 3.1 outward currents were reduced by 80% (digitoxin, 1 Hz) and 78% (digoxin, 1 Hz). Digitoxin inhibited K 2P 3.1 currents with an IC 50 value of 7.4 µ M. Outward rectification properties of the channel were not affected. Mutagenesis studies revealed that amino acid residues located at the cytoplasmic site of the K 2P 3.1 channel pore form parts of a molecular binding site for cardiac glycosides. In conclusion, cardiac glycosides target human K 2P channels. The antiarrhythmic significance of repolarizing atrial K 2P 3.1 current block by digoxin and digitoxin requires validation in translational and clinical studies.

New Targets for Old Drugs: Cardiac Glycosides Inhibit Atrial-Specific K2P3.1 (TASK-1) Channels

New Targets for Old Drugs: Cardiac Glycosides Inhibit Atrial-Specific K_2P3.1 (TASK-1) Channels