PA-6 inhibits inward rectifier currents carried by V93I and D172N gain-of-function K2.1 channels, but increases channel protein expression.

Background: The inward rectifier potassium current I contributes to a stable resting membrane potential and phase 3 repolarization of the cardiac action potential. KCNJ2 gain-of-function mutations V93I and D172N associate with increased I, short QT syndrome type 3 and congenital atrial fibrillation. Pentamidine-Analogue 6 (PA-6) is an efficient (IC = 14 nM with inside-out patch clamp methodology) and specific I inhibitor that interacts with the cytoplasmic pore region of the K2.

Class III antiarrhythmic drugs amiodarone and dronedarone impair K 2.1 backward trafficking.

Drug-induced ion channel trafficking disturbance can cause cardiac arrhythmias. The subcellular level at which drugs interfere in trafficking pathways is largely unknown. K 2.