Cardiac K2P13.1 (THIK-1) two-pore-domain K+ channels: Pharmacological regulation and remodeling in atrial fibrillation

Cardiac two-pore-domain potassium (K-2P) channels have been proposed as novel antiarrhythmic targets. K(2P)13.1 (THIK-1) channels are expressed in the human heart, and atrial K(2P)13.1 levels are reduced in patients with atrial fibrillation (AF) or heart failure. The first objective of this study was to investigate acute effects of antiarrhythmic drugs on human K(2P)13.1 currents. Second, we assessed atrial K(2P)13.1 remodeling in AF pigs to validate the porcine model for future translational evaluation of K(2P)13.1-based antiarrhythmic concepts. K(2P)13.1 protein expression was studied in domestic pigs during AF induced by atrial burst pacing. AF was associated with 66% reduction of K(2P)13.1 levels in the right atrium at 21-day follow-up. Voltage clamp electrophysiology was employed to elucidate human K(2P)13.1 channel pharmacology in Xenopus oocytes. Propafenone (-26%; 100 mu M), mexiletine (-75%; 1.5 mM), propranolol (-38%; 200 mu M) and lidocaine (-59%; 100 mu M) significantly inhibited K(2P)13.1 currents. By contrast, K(2P)13.1 channels were not markedly affected by quinidine, carvedilol, metoprolol, amiodarone and verapamil. Concentration-dependent K(2P)13.1 blockade by mexiletine occurred rapidly with membrane depolarization and was frequency-independent. Mexiletine reduced K(2P)13.1 open rectification properties and shifted current-voltage relationships towards more negative potentials. In conclusion, atrial expression and AF-associated downregulation of K(2P)13.1 channels in a porcine model resemble human findings and support a general role for K(2P)13.1 in AF pathophysiology. K(2P)13.1 current sensitivity to antiarrhythmic drugs provides a starting point for further development of an emerging antiarrhythmic paradigm. (C) 2018 Elsevier Ltd. All rights reserved.