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Naunyn Schmiedebergs Arch Pharmacol
2014 Dec 01;38712:1153-61. doi: 10.1007/s00210-014-1045-6.
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Class III antiarrhythmic drug dronedarone inhibits cardiac inwardly rectifying Kir2.1 channels through binding at residue E224.
Xynogalos P
,
Seyler C
,
Scherer D
,
Koepple C
,
Scholz EP
,
Thomas D
,
Katus HA
,
Zitron E
.
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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.
Amorós,
Propafenone blocks human cardiac Kir2.x channels by decreasing the negative electrostatic charge in the cytoplasmic pore.
2013, Pubmed
Amorós,
Propafenone blocks human cardiac Kir2.x channels by decreasing the negative electrostatic charge in the cytoplasmic pore.
2013,
Pubmed
Bosch,
Ionic mechanisms of electrical remodeling in human atrial fibrillation.
1999,
Pubmed
Bosch,
Electrophysiologic effects of chronic amiodarone therapy and hypothyroidism, alone and in combination, on guinea pig ventricular myocytes.
1999,
Pubmed
Connolly,
Dronedarone in high-risk permanent atrial fibrillation.
2011,
Pubmed
Danelich,
Clinical update on the management of atrial fibrillation.
2013,
Pubmed
Dhamoon,
The inward rectifier current (IK1) controls cardiac excitability and is involved in arrhythmogenesis.
2005,
Pubmed
Dobrev,
Molecular basis of downregulation of G-protein-coupled inward rectifying K(+) current (I(K,ACh) in chronic human atrial fibrillation: decrease in GIRK4 mRNA correlates with reduced I(K,ACh) and muscarinic receptor-mediated shortening of action potentials.
2001,
Pubmed
Du,
Characteristic interactions with phosphatidylinositol 4,5-bisphosphate determine regulation of kir channels by diverse modulators.
2004,
Pubmed
,
Xenbase
Ferrer,
Carvedilol inhibits Kir2.3 channels by interference with PIP₂-channel interaction.
2011,
Pubmed
Gautier,
Electrophysiologic characterization of dronedarone in guinea pig ventricular cells.
2003,
Pubmed
Girmatsion,
Changes in microRNA-1 expression and IK1 up-regulation in human atrial fibrillation.
2009,
Pubmed
Hilgemann,
Cytoplasmic ATP-dependent regulation of ion transporters and channels: mechanisms and messengers.
1997,
Pubmed
Hohnloser,
Effect of dronedarone on cardiovascular events in atrial fibrillation.
2009,
Pubmed
Logothetis,
Diverse Kir modulators act in close proximity to residues implicated in phosphoinositide binding.
2007,
Pubmed
Lopes,
Alterations in conserved Kir channel-PIP2 interactions underlie channelopathies.
2002,
Pubmed
,
Xenbase
López-Izquierdo,
Mechanisms for Kir channel inhibition by quinacrine: acute pore block of Kir2.x channels and interference in PIP2 interaction with Kir2.x and Kir6.2 channels.
2011,
Pubmed
López-Izquierdo,
The antimalarial drug mefloquine inhibits cardiac inward rectifier K+ channels: evidence for interference in PIP2-channel interaction.
2011,
Pubmed
Madeja,
Follicular tissues reduce drug effects on ion channels in oocytes of Xenopus laevis.
1997,
Pubmed
,
Xenbase
Melnyk,
Differential distribution of Kir2.1 and Kir2.3 subunits in canine atrium and ventricle.
2002,
Pubmed
Noujaim,
Structural bases for the different anti-fibrillatory effects of chloroquine and quinidine.
2011,
Pubmed
Noujaim,
Up-regulation of the inward rectifier K+ current (I K1) in the mouse heart accelerates and stabilizes rotors.
2007,
Pubmed
Noujaim,
Specific residues of the cytoplasmic domains of cardiac inward rectifier potassium channels are effective antifibrillatory targets.
2010,
Pubmed
Ponce-Balbuena,
Tamoxifen inhibits inward rectifier K+ 2.x family of inward rectifier channels by interfering with phosphatidylinositol 4,5-bisphosphate-channel interactions.
2009,
Pubmed
Preisig-Müller,
Heteromerization of Kir2.x potassium channels contributes to the phenotype of Andersen's syndrome.
2002,
Pubmed
,
Xenbase
Rodríguez-Menchaca,
The molecular basis of chloroquine block of the inward rectifier Kir2.1 channel.
2008,
Pubmed
Rohács,
Specificity of activation by phosphoinositides determines lipid regulation of Kir channels.
2003,
Pubmed
,
Xenbase
Sato,
Amiodarone blocks the inward rectifier potassium channel in isolated guinea pig ventricular cells.
1994,
Pubmed
Schimpf,
Short QT syndrome: successful prevention of sudden cardiac death in an adolescent by implantable cardioverter-defibrillator treatment for primary prophylaxis.
2005,
Pubmed
Schimpf,
Short QT syndrome.
2005,
Pubmed
Schram,
Barium block of Kir2 and human cardiac inward rectifier currents: evidence for subunit-heteromeric contribution to native currents.
2003,
Pubmed
,
Xenbase
Singh,
Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter.
2007,
Pubmed
Thomas,
Acute effects of dronedarone on both components of the cardiac delayed rectifier K+ current, HERG and KvLQT1/minK potassium channels.
2003,
Pubmed
,
Xenbase
Tristani-Firouzi,
Functional and clinical characterization of KCNJ2 mutations associated with LQT7 (Andersen syndrome).
2002,
Pubmed
,
Xenbase
Tristani-Firouzi,
Kir 2.1 channelopathies: the Andersen-Tawil syndrome.
2010,
Pubmed
Van Wagoner,
Outward K+ current densities and Kv1.5 expression are reduced in chronic human atrial fibrillation.
1997,
Pubmed
Varró,
Electrophysiological effects of dronedarone (SR 33589), a noniodinated amiodarone derivative in the canine heart: comparison with amiodarone.
2001,
Pubmed
Voigt,
Left-to-right atrial inward rectifier potassium current gradients in patients with paroxysmal versus chronic atrial fibrillation.
2010,
Pubmed
Wang,
Differential distribution of inward rectifier potassium channel transcripts in human atrium versus ventricle.
1998,
Pubmed
Xia,
A Kir2.1 gain-of-function mutation underlies familial atrial fibrillation.
2005,
Pubmed
Xie,
Phosphatidylinositol-4,5-bisphosphate (PIP2) regulation of strong inward rectifier Kir2.1 channels: multilevel positive cooperativity.
2008,
Pubmed
,
Xenbase
Zaritsky,
Targeted disruption of Kir2.1 and Kir2.2 genes reveals the essential role of the inwardly rectifying K(+) current in K(+)-mediated vasodilation.
2000,
Pubmed
Zobel,
Molecular dissection of the inward rectifier potassium current (IK1) in rabbit cardiomyocytes: evidence for heteromeric co-assembly of Kir2.1 and Kir2.2.
2003,
Pubmed
de Boer,
The anti-protozoal drug pentamidine blocks KIR2.x-mediated inward rectifier current by entering the cytoplasmic pore region of the channel.
2010,
Pubmed
