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Naunyn Schmiedebergs Arch Pharmacol
2012 Oct 01;38510:1003-16. doi: 10.1007/s00210-012-0780-9.
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Novel electrophysiological properties of dronedarone: inhibition of human cardiac two-pore-domain potassium (K2P) channels.
Schmidt C, Wiedmann F, Schweizer PA, Becker R, Katus HA, Thomas D.
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Dronedarone is currently used for the treatment of paroxysmal and persistent atrial fibrillation (AF). Pharmacological inhibition of cardiac two-pore-domain potassium (K(2P)) channels results in action potential prolongation and has recently been proposed as novel antiarrhythmic strategy. We hypothesized that blockade of human K(2P) channels contributes to the electrophysiological efficacy of dronedarone in AF. Two-electrode voltage clamp and whole-cell patch clamp electrophysiology was used to record K(2P) currents from Xenopus oocytes and Chinese hamster ovary cells. All functional human K(2P) channels were screened for dronedarone sensitivity, revealing significant and concentration-dependent inhibition of cardiac K(2P)2.1 (TREK1; IC(50) = 26.7 μM) and K(2P)3.1 channels (TASK1; IC(50) = 18.7 μM) with maximum current reduction of 60.3 and 65.5 % in oocytes. IC(50) values obtained from mammalian cells yielded 6.1 μM (K(2P)2.1) and 5.2 μM (K(2P)3.1). The molecular mechanism of action was studied in detail. Dronedarone block affected open and closed channels. K(2P)3.1 currents were reduced in frequency-dependent fashion in contrast to K(2P)2.1. Mutagenesis studies revealed that amino acid residues implicated in K(2P)3.1 drug interactions were not required for dronedarone blockade. The class III antiarrhythmic drug dronedarone targets multiple human cardiac two-pore-domain potassium channels, including atrial-selective K(2P)3.1 currents. K(2P) current inhibition by dronedarone represents a previously unrecognized mechanism of action that extends the multichannel blocking profile of the drug.
Aimond,
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2000, Pubmed
Aimond,
Cellular and in vivo electrophysiological effects of dronedarone in normal and postmyocardial infarcted rats.
2000,
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2000,
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The TASK family: two-pore domain background K+ channels.
2003,
Pubmed Bockenhauer,
KCNK2: reversible conversion of a hippocampal potassium leak into a voltage-dependent channel.
2001,
Pubmed
,
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2011,
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Crystal structure of the human K2P TRAAK, a lipid- and mechano-sensitive K+ ion channel.
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Dronedarone in high-risk permanent atrial fibrillation.
2011,
Pubmed Decher,
Characterization of TASK-4, a novel member of the pH-sensitive, two-pore domain potassium channel family.
2001,
Pubmed
,
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2011,
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2010,
Pubmed Donner,
Functional role of TASK-1 in the heart: studies in TASK-1-deficient mice show prolonged cardiac repolarization and reduced heart rate variability.
2011,
Pubmed Dorian,
Clinical pharmacology of dronedarone: implications for the therapy of atrial fibrillation.
2010,
Pubmed Ehrlich,
Novel approaches for pharmacological management of atrial fibrillation.
2009,
Pubmed Ehrlich,
Atrial-selective approaches for the treatment of atrial fibrillation.
2008,
Pubmed Ellinghaus,
Comparing the global mRNA expression profile of human atrial and ventricular myocardium with high-density oligonucleotide arrays.
2005,
Pubmed Feliciangeli,
Does sumoylation control K2P1/TWIK1 background K+ channels?
2007,
Pubmed
,
Xenbase Gautier,
Electrophysiologic characterization of dronedarone in guinea pig ventricular cells.
2003,
Pubmed Gierten,
Regulation of two-pore-domain (K2P) potassium leak channels by the tyrosine kinase inhibitor genistein.
2008,
Pubmed
,
Xenbase Gierten,
The human cardiac K2P3.1 (TASK-1) potassium leak channel is a molecular target for the class III antiarrhythmic drug amiodarone.
2010,
Pubmed
,
Xenbase Gierten,
Identification and functional characterization of zebrafish K(2P)10.1 (TREK2) two-pore-domain K(+) channels.
2012,
Pubmed
,
Xenbase Goonetilleke,
TREK-1 K(+) channels in the cardiovascular system: their significance and potential as a therapeutic target.
2012,
Pubmed Guillemare,
Inhibitory effects of dronedarone on muscarinic K+ current in guinea pig atrial cells.
2000,
Pubmed Gurney,
Two-pore potassium channels in the cardiovascular system.
2009,
Pubmed Hohnloser,
Effect of dronedarone on cardiovascular events in atrial fibrillation.
2009,
Pubmed Iwasaki,
Atrial fibrillation pathophysiology: implications for management.
2011,
Pubmed Kathofer,
The novel antiarrhythmic drug dronedarone: comparison with amiodarone.
2005,
Pubmed Lalevée,
Effects of amiodarone and dronedarone on voltage-dependent sodium current in human cardiomyocytes.
2003,
Pubmed Lalevée,
Control of cardiac rhythm by ORK1, a Drosophila two-pore domain potassium channel.
2006,
Pubmed Limberg,
TASK-1 channels may modulate action potential duration of human atrial cardiomyocytes.
2011,
Pubmed
,
Xenbase Liu,
Heterogeneous expression of tandem-pore K+ channel genes in adult and embryonic rat heart quantified by real-time polymerase chain reaction.
2004,
Pubmed Lopes,
Proton block and voltage gating are potassium-dependent in the cardiac leak channel Kcnk3.
2000,
Pubmed
,
Xenbase Marbán,
Cardiac channelopathies.
2002,
Pubmed Milac,
Structural models of TREK channels and their gating mechanism.
2011,
Pubmed Miller,
Crystal structure of the human two-pore domain potassium channel K2P1.
2012,
Pubmed Obers,
Multiple mechanisms of hERG liability: K+ current inhibition, disruption of protein trafficking, and apoptosis induced by amoxapine.
2010,
Pubmed
,
Xenbase Patel,
Properties and modulation of mammalian 2P domain K+ channels.
2001,
Pubmed Putzke,
The acid-sensitive potassium channel TASK-1 in rat cardiac muscle.
2007,
Pubmed
,
Xenbase Rahm,
PKC-dependent activation of human K(2P) 18.1 K(+) channels.
2012,
Pubmed
,
Xenbase Rajan,
Sumoylation silences the plasma membrane leak K+ channel K2P1.
2005,
Pubmed
,
Xenbase Ravens,
Novel pharmacological approaches for antiarrhythmic therapy.
2010,
Pubmed Ridley,
High affinity HERG K(+) channel blockade by the antiarrhythmic agent dronedarone: resistance to mutations of the S6 residues Y652 and F656.
2004,
Pubmed Schweizer,
Dronedarone: current evidence for its safety and efficacy in the management of atrial fibrillation.
2011,
Pubmed Seyler,
TASK1 (K(2P)3.1) K(+) channel inhibition by endothelin-1 is mediated through Rho kinase-dependent phosphorylation.
2012,
Pubmed
,
Xenbase Staudacher,
hERG K+ channel-associated cardiac effects of the antidepressant drug desipramine.
2011,
Pubmed
,
Xenbase Staudacher,
Alternative splicing determines mRNA translation initiation and function of human K(2P)10.1 K+ channels.
2011,
Pubmed
,
Xenbase Staudacher,
Carvedilol targets human K2P 3.1 (TASK1) K+ leak channels.
2011,
Pubmed
,
Xenbase Streit,
A specific two-pore domain potassium channel blocker defines the structure of the TASK-1 open pore.
2011,
Pubmed
,
Xenbase Thomas,
High-affinity blockade of human ether-a-go-go-related gene human cardiac potassium channels by the novel antiarrhythmic drug BRL-32872.
2001,
Pubmed
,
Xenbase Thomas,
Acute effects of dronedarone on both components of the cardiac delayed rectifier K+ current, HERG and KvLQT1/minK potassium channels.
2003,
Pubmed
,
Xenbase Thomas,
Alternative translation initiation in rat brain yields K2P2.1 potassium channels permeable to sodium.
2008,
Pubmed
,
Xenbase Varró,
Electrophysiological effects of dronedarone (SR 33589), a noniodinated amiodarone derivative in the canine heart: comparison with amiodarone.
2001,
Pubmed Voigt,
Inhibition of IK,ACh current may contribute to clinical efficacy of class I and class III antiarrhythmic drugs in patients with atrial fibrillation.
2010,
Pubmed Watanabe,
Acute inhibitory effect of dronedarone, a noniodinated benzofuran analogue of amiodarone, on Na+/Ca2+ exchange current in guinea pig cardiac ventricular myocytes.
2008,
Pubmed Xian Tao Li,
The stretch-activated potassium channel TREK-1 in rat cardiac ventricular muscle.
2006,
Pubmed Zhang,
The hERG K(+) channel S4 domain L532P mutation: characterization at 37°C.
2011,
Pubmed
