Cardiovascular pharmacology of K_2P17.1 (TASK-4, TALK-2) two-pore-domain K⁺ channels

K_2P17.1 (TASK-4, TALK-2) potassium channels are expressed in the heart and represent potential targets for pharmacological management of atrial and ventricular arrhythmias. Reduced K_2P17.1 expression was found in atria and ventricles of heart failure (HF) patients. Modulation of K_2P17.1 currents by antiarrhythmic compounds has not been comprehensively studied to date. The objective of this study was to investigate acute effects of clinically relevant antiarrhythmic drugs on human K_2P17.1 channels to provide a more complete picture of K_2P17.1 electropharmacology. Whole-cell patch clamp and two-electrode voltage clamp electrophysiology was employed to study human K_2P17.1 channel pharmacology. K_2P17.1 channels expressed in Xenopus laevis oocytes were screened for sensitivity to antiarrhythmic drugs, revealing significant activation by propafenone (+ 296%; 100 μM), quinidine (+ 58%; 100 μM), mexiletine (+ 21%; 100 μM), propranolol (+ 139%; 100 μM), and metoprolol (+ 17%; 100 μM) within 60 min. In addition, the currents were inhibited by amiodarone (- 13%; 100 μM), sotalol (- 10%; 100 μM), verapamil (- 21%; 100 μM), and ranolazine (- 8%; 100 μM). K_2P17.1 channels were not significantly affected by ajmaline and carvedilol. Concentration-dependent K_2P17.1 activation by propafenone was characterized in more detail. The onset of activation was fast, and current-voltage relationships were not modulated by propafenone. K_2P17.1 activation was confirmed in mammalian Chinese hamster ovary cells, revealing 7.8-fold current increase by 100 μM propafenone. Human K_2P17.1 channels were sensitive to multiple antiarrhythmic drugs. Differential pharmacological regulation of repolarizing K_2P17.1 background K⁺ channels may be employed for personalized antiarrhythmic therapy.