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Cardiovascular pharmacology of K2P17.1 (TASK-4, TALK-2) two-pore-domain K+ channels

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Abstract

K2P17.1 (TASK-4, TALK-2) potassium channels are expressed in the heart and represent potential targets for pharmacological management of atrial and ventricular arrhythmias. Reduced K2P17.1 expression was found in atria and ventricles of heart failure (HF) patients. Modulation of K2P17.1 currents by antiarrhythmic compounds has not been comprehensively studied to date. The objective of this study was to investigate acute effects of clinically relevant antiarrhythmic drugs on human K2P17.1 channels to provide a more complete picture of K2P17.1 electropharmacology. Whole-cell patch clamp and two-electrode voltage clamp electrophysiology was employed to study human K2P17.1 channel pharmacology. K2P17.1 channels expressed in Xenopus laevis oocytes were screened for sensitivity to antiarrhythmic drugs, revealing significant activation by propafenone (+ 296%; 100 μM), quinidine (+ 58%; 100 μM), mexiletine (+ 21%; 100 μM), propranolol (+ 139%; 100 μM), and metoprolol (+ 17%; 100 μM) within 60 min. In addition, the currents were inhibited by amiodarone (− 13%; 100 μM), sotalol (− 10%; 100 μM), verapamil (− 21%; 100 μM), and ranolazine (− 8%; 100 μM). K2P17.1 channels were not significantly affected by ajmaline and carvedilol. Concentration-dependent K2P17.1 activation by propafenone was characterized in more detail. The onset of activation was fast, and current-voltage relationships were not modulated by propafenone. K2P17.1 activation was confirmed in mammalian Chinese hamster ovary cells, revealing 7.8-fold current increase by 100 μM propafenone. Human K2P17.1 channels were sensitive to multiple antiarrhythmic drugs. Differential pharmacological regulation of repolarizing K2P17.1 background K+ channels may be employed for personalized antiarrhythmic therapy.

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Acknowledgements

We thank Simone Bauer, Christine Jeckel, Jennifer Kleist, Axel Schöffel, Kai Sona and Nadine Weiberg for excellent technical assistance. This work was supported in part by research grants from the University of Heidelberg, Faculty of Medicine (Physician Scientist Program to I.S. and to A.K.R.), from the German Cardiac Society (German Cardiac Society Scholarship to I.S. and to A.K.R., Otto Hess Scholarship to S.S.), from the German Heart Foundation/German Foundation of Heart Research (Kaltenbach Scholarship to D.G., project F/08/14 to D.T.), from the Else Kröner-Fresenius-Stiftung (2014_A242 to D.T.), from the Joachim Siebeneicher Foundation (to D.T.), from the Deutsche Forschungsgemeinschaft (German Research Foundation; SCHW 1611/1-1 to P.A.S., TH 1120/8-1 to D.T.), and from the Ministry of Science, Research and the Arts Baden-Wuerttemberg (Sonderlinie Medizin to D.T.). C.I. and T.W. were supported by the Cardiology Career Program of the Department of Cardiology, University of Heidelberg. P.A.S was supported by the Heidelberg Research Centre for Molecular Medicine (Senior Career Fellowship). Additionally, portions of this work were supported by NIH/NHLBI 1R01HL124245 (to I.D.) and an American Heart Association Pre-Doctoral Fellowship from the Great Rivers Affiliate 15PRE25700037 (to S.C.).

Author contribution statement

IS, CI, ID, AKR and DT conceived and designed research. IS, CI, SC, ID, SS, DG, MEM, TW and AKR conducted experiments. CM contributed new analytical tools. IS, CI, SC, ID, DG, MEM, TW, AKR, PAS, HAK and DT analyzed data and participated in data interpretation. IS, CI, DG, MEM, TW, AKR and DT wrote the manuscript. IS, CI, SC, ID, SS, DG, MEM, TW, AKR, PAS, HAK and DT critically revised the manuscript for important intellectual content. All authors read and approved the manuscript.

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Authors and Affiliations

  1. Department of Cardiology, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany

    Ingo Staudacher, Claudius Illg, Sebastian Seehausen, Dominik Gramlich, Mara Elena Müller, Teresa Wieder, Ann-Kathrin Rahm, Patrick A. Schweizer, Hugo A. Katus & Dierk Thomas

  2. HCR (Heidelberg Center for Heart Rhythm Disorders), University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany

    Ingo Staudacher, Claudius Illg, Sebastian Seehausen, Dominik Gramlich, Mara Elena Müller, Teresa Wieder, Ann-Kathrin Rahm, Patrick A. Schweizer, Hugo A. Katus & Dierk Thomas

  3. Department of Physiology and Biophysics, Case Western Reserve University, 10900 Euclid Ave, Cleveland, OH, 44106, USA

    Sam Chai & Isabelle Deschenes

  4. Heart and Vascular Research Center, Department of Medicine, MetroHealth Campus, Case Western Reserve University, 2500 MetroHealth Drive, Cleveland, OH, 44109, USA

    Sam Chai & Isabelle Deschenes

  5. Institute for Physiology and Pathophysiology, University of Heidelberg, Im Neuenheimer Feld 326, 69120, Heidelberg, Germany

    Christina Mayer

  6. DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, University of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany

    Patrick A. Schweizer, Hugo A. Katus & Dierk Thomas

  7. Heidelberg Research Center for Molecular Medicine (HRCMM), Im Neuenheimer Feld 350, 69120, Heidelberg, Germany

    Patrick A. Schweizer

Authors
  1. Ingo Staudacher
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  2. Claudius Illg
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  3. Sam Chai
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  8. Teresa Wieder
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  9. Ann-Kathrin Rahm
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  12. Hugo A. Katus
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  13. Dierk Thomas
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Corresponding author

Correspondence to Dierk Thomas.

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Ethics statement

This study has been carried out in accordance with the Guide for the Care and Use of Laboratory Animals as adopted and promulgated by the US National Institutes of Health (NIH publication no. 85-23, revised 1985), and the current version of the German Law on the Protection of Animals was followed. The investigation conforms to the Directive 2010/63/EU of the European Parliament. The study protocol involving human tissue samples was approved by the ethics committee of the University of Heidelberg (Germany; Medical Faculty Heidelberg, S-017/2013). Written informed consent was obtained from all patients, and the study was conducted in accordance with the Declaration of Helsinki. Approval for experiments involving Xenopus laevis was granted by the local Animal Welfare Committee (institutional approval numbers A-38/11 and G-221/12).

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Staudacher, I., Illg, C., Chai, S. et al. Cardiovascular pharmacology of K2P17.1 (TASK-4, TALK-2) two-pore-domain K+ channels. Naunyn-Schmiedeberg's Arch Pharmacol 391, 1119–1131 (2018). https://doi.org/10.1007/s00210-018-1535-z

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