The human cardiac K2P3.1 (TASK-1) potassium leak channel is a molecular target for the class III antiarrhythmic drug amiodarone.
Two-pore-domain (K(2P)) potassium channels mediate background potassium currents, stabilizing resting membrane potential and expediting action potential repolarization. In the heart, K(2P)3.1 (TASK-1) channels are implicated in the cardiac plateau current, I ( KP ). Class III antiarrhythmic drugs target cardiac K(+) currents, resulting in action potential prolongation and suppression of atrial and ventricular arrhythmias. The objective of this study was to investigate acute effects of the class III antiarrhythmic drug amiodarone on human K(2P)3.1 channels. Potassium currents were recorded from Xenopus oocytes using the two-microelectrode voltage clamp technique. Amiodarone produced concentration-dependent inhibition of hK(2P)3.1 currents (IC(50) = 0.40 microM) with maximum current reduction of 58.1%. Open rectification properties that are characteristic to hK(2P)3.1 currents were not altered by amiodarone. Channels were blocked in open and closed states in reverse frequency-dependent manner. hK(2P)3.1 channel inhibition was voltage-independent at voltages between -40 and +60 mV. Modulation of protein kinase C activity by amiodarone does not contribute to hK(2P)3.1 current reduction, as pre-treatment with the protein kinase C inhibitor, staurosporine, did not affect amiodarone block. Amiodarone is an inhibitor of cardiac hK(2P)3.1 background channels. Amiodarone blockade of hK(2P)3.1 may cause prolongation of cardiac repolarization and action potential duration in patients with high individual plasma concentrations, possibly contributing to the antiarrhythmic efficacy of the class III drug.
Department of Cardiology, Medical University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.
Jakob
J
Gierten
Eckhard
E
Ficker
Ramona
R
Bloehs
Patrick A
PA
Schweizer
Edgar
E
Zitron
Eberhard
E
Scholz
Christoph
C
Karle
Hugo A
HA
Katus
Dierk
D
Thomas
D000200:Action Potentials / Q000187:drug effects; D000638:Amiodarone / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D003001:Cloning, Molecular; D004305:Dose-Response Relationship, Drug; D005260:Female; D009206:Myocardium / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors*; D009865:Oocytes / Q000166:cytology / Q000378:metabolism; D018408:Patch-Clamp Techniques; D024683:Potassium Channels, Tandem Pore Domain / Q000037:antagonists & inhibitors*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D019311:Staurosporine / Q000494:pharmacology; D014982:Xenopus laevis
D000889:Anti-Arrhythmia Agents; D009419:Nerve Tissue Proteins; D024683:Potassium Channels, Tandem Pore Domain; C420132:potassium channel subfamily K member 3; D011493:Protein Kinase C; D019311:Staurosporine; D000638:Amiodarone