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The human cardiac K2P3.1 (TASK-1) potassium leak channel is a molecular target for the class III antiarrhythmic drug amiodarone

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Abstract

Two-pore-domain (K2P) potassium channels mediate background potassium currents, stabilizing resting membrane potential and expediting action potential repolarization. In the heart, K2P3.1 (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 K2P3.1 channels. Potassium currents were recorded from Xenopus oocytes using the two-microelectrode voltage clamp technique. Amiodarone produced concentration-dependent inhibition of hK2P3.1 currents (IC50 = 0.40 µM) with maximum current reduction of 58.1%. Open rectification properties that are characteristic to hK2P3.1 currents were not altered by amiodarone. Channels were blocked in open and closed states in reverse frequency-dependent manner. hK2P3.1 channel inhibition was voltage-independent at voltages between −40 and +60 mV. Modulation of protein kinase C activity by amiodarone does not contribute to hK2P3.1 current reduction, as pre-treatment with the protein kinase C inhibitor, staurosporine, did not affect amiodarone block. Amiodarone is an inhibitor of cardiac hK2P3.1 background channels. Amiodarone blockade of hK2P3.1 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.

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Acknowledgments

We are grateful to Dr. Steve Goldstein for providing the cDNA clone encoding hK2P3.1. This work was supported in part by grants from the Deutsche Forschungsgemeinschaft (project KA 1714/1-1 to C.K.), from the German Cardiac Society (Max Schaldach Research Scholarship to D.T.), from the University of Heidelberg (FRONTIERS program), from the ADUMED-Foundation (to D.T.), and from the National Institutes of Health (HL71789 to E.F.). J.G. is a fellow of the MD/PhD program at the University of Heidelberg.

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Correspondence to Dierk Thomas.

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Gierten, J., Ficker, E., Bloehs, R. et al. The human cardiac K2P3.1 (TASK-1) potassium leak channel is a molecular target for the class III antiarrhythmic drug amiodarone. Naunyn-Schmied Arch Pharmacol 381, 261–270 (2010). https://doi.org/10.1007/s00210-009-0454-4

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