title: Class III antiarrhythmic drug dronedarone inhibits cardiac inwardly rectifying Kir2.1 channels through binding at residue E224.
abstract: Dronedarone is a novel class III antiarrhythmic drug that is widely used in atrial fibrillation. It has been shown in native cardiomyocytes that dronedarone inhibits cardiac inwardly rectifying current IK1 at high concentrations, which may contribute both its antifibrillatory efficacy and its potential proarrhythmic side effects. However, the underlying mechanism has not been studied in further detail to date. In the mammalian heart, heterotetrameric assembly of Kir2.x channels is the molecular basis of IK1 current. Therefore, we studied the effects of dronedarone on wild-type and mutant Kir2.x channels in the Xenopus oocyte expression system. Dronedarone inhibited Kir2.1 currents but had no effect on Kir2.2 or Kir2.3 currents. Onset of block was slow but completely reversible upon washout. Blockade of Kir2.1 channels did not exhibit strong voltage dependence or frequency dependence. In a screening with different Kir2.1 mutants lacking specific binding sites within the cytoplasmic pore region, we found that residue E224 is essential for binding of dronedarone to Kir2.1 channels. In conclusion, direct block of Kir2.1 channel subunits by dronedarone through binding at E224 may underlie its inhibitory effects on cardiac IK1 current.
authors.affiliation: Department of Cardiology, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany, panagiotis.xynogalos@med.uni-heidelberg.de.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Xynogalos
authors.forename: Claudia
authors.initials: C
authors.lastname: Seyler
authors.forename: Daniel
authors.initials: D
authors.lastname: Scherer
authors.forename: Christoph
authors.initials: C
authors.lastname: Koepple
authors.forename: Eberhard P
authors.initials: EP
authors.lastname: Scholz
authors.forename: Dierk
authors.initials: D
authors.lastname: Thomas
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.forename: Edgar
authors.initials: E
authors.lastname: Zitron
mesh_terms: D000638:Amiodarone / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001665:Binding Sites; D000077764:Dronedarone; D009865:Oocytes; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011485:Protein Binding; D014982:Xenopus laevis
chemical_list: D000889:Anti-Arrhythmia Agents; C489461:Kir2.1 channel; C489463:Kir2.2 channel; D024661:Potassium Channels, Inwardly Rectifying; D000077764:Dronedarone; D000638:Amiodarone