New Targets for Old Drugs: Cardiac Glycosides Inhibit Atrial-Specific K3.1 (TASK-1) Channels.

Cardiac glycosides have been used in the treatment of arrhythmias for more than 200 years. Two-pore-domain (K) potassium channels regulate cardiac action potential repolarization. Recently, K3.1 [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 channels contributes to the mechanism of action of digitoxin and digoxin. All functional human K channels were screened for interactions with cardiac glycosides. Human K channel subunits were expressed in oocytes, and voltage clamp electrophysiology was used to record K currents. Digitoxin significantly inhibited K3.1 and K16.1 channels. By contrast, digoxin displayed isolated inhibitory effects on K3.1. K3.1 outward currents were reduced by 80% (digitoxin, 1 Hz) and 78% (digoxin, 1 Hz). Digitoxin inhibited K3.1 currents with an IC value of 7.4 M. Outward rectification properties of the channel were not affected. Mutagenesis studies revealed that amino acid residues located at the cytoplasmic site of the K3.1 channel pore form parts of a molecular binding site for cardiac glycosides. In conclusion, cardiac glycosides target human K channels. The antiarrhythmic significance of repolarizing atrial K3.1 current block by digoxin and digitoxin requires validation in translational and clinical studies.