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Cardiac K2P13.1 (THIK-1) two-pore-domain K+ channels: Pharmacological regulation and remodeling in atrial fibrillation.
Prog Biophys Mol Biol 2019; 144:128-138PB

Abstract

Cardiac two-pore-domain potassium (K2P) channels have been proposed as novel antiarrhythmic targets. K2P13.1 (THIK-1) channels are expressed in the human heart, and atrial K2P13.1 levels are reduced in patients with atrial fibrillation (AF) or heart failure. The first objective of this study was to investigate acute effects of antiarrhythmic drugs on human K2P13.1 currents. Second, we assessed atrial K2P13.1 remodeling in AF pigs to validate the porcine model for future translational evaluation of K2P13.1-based antiarrhythmic concepts. K2P13.1 protein expression was studied in domestic pigs during AF induced by atrial burst pacing. AF was associated with 66% reduction of K2P13.1 levels in the right atrium at 21-day follow-up. Voltage clamp electrophysiology was employed to elucidate human K2P13.1 channel pharmacology in Xenopus oocytes. Propafenone (-26%; 100 μM), mexiletine (-75%; 1.5 mM), propranolol (-38%; 200 μM), and lidocaine (-59%; 100 μM) significantly inhibited K2P13.1 currents. By contrast, K2P13.1 channels were not markedly affected by quinidine, carvedilol, metoprolol, amiodarone and verapamil. Concentration-dependent K2P13.1 blockade by mexiletine occurred rapidly with membrane depolarization and was frequency-independent. Mexiletine reduced K2P13.1 open rectification properties and shifted current-voltage relationships towards more negative potentials. In conclusion, atrial expression and AF-associated downregulation of K2P13.1 channels in a porcine model resemble human findings and support a general role for K2P13.1 in AF pathophysiology. K2P13.1 current sensitivity to antiarrhythmic drugs provides a starting point for further development of an emerging antiarrhythmic paradigm.

Authors+Show Affiliations

Department of Cardiology, Medical University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany; HCR (Heidelberg Center for Heart Rhythm Disorders), University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.Department of Cardiology, Medical University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany; HCR (Heidelberg Center for Heart Rhythm Disorders), University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.Department of Cardiology, Medical University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany; HCR (Heidelberg Center for Heart Rhythm Disorders), University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.Department of Cardiology, Medical University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany; HCR (Heidelberg Center for Heart Rhythm Disorders), University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.Department of Cardiology, Medical University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany; HCR (Heidelberg Center for Heart Rhythm Disorders), University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany; DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg/Mannheim, University of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany; Heidelberg Research Center for Molecular Medicine (HRCMM), Im Neuenheimer Feld 350, 69120, Heidelberg, Germany.Department of Cardiology, Medical University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany; HCR (Heidelberg Center for Heart Rhythm Disorders), University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany; DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg/Mannheim, University of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.Department of Cardiology, Medical University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany; HCR (Heidelberg Center for Heart Rhythm Disorders), University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany; DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg/Mannheim, University of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany. Electronic address: dierk.thomas@med.uni-heidelberg.de.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

31182191

Citation

Staudacher, Ingo, et al. "Cardiac K2P13.1 (THIK-1) Two-pore-domain K+ Channels: Pharmacological Regulation and Remodeling in Atrial Fibrillation." Progress in Biophysics and Molecular Biology, vol. 144, 2019, pp. 128-138.
Staudacher I, Seehausen S, Illg C, et al. Cardiac K2P13.1 (THIK-1) two-pore-domain K+ channels: Pharmacological regulation and remodeling in atrial fibrillation. Prog Biophys Mol Biol. 2019;144:128-138.
Staudacher, I., Seehausen, S., Illg, C., Lugenbiel, P., Schweizer, P. A., Katus, H. A., & Thomas, D. (2019). Cardiac K2P13.1 (THIK-1) two-pore-domain K+ channels: Pharmacological regulation and remodeling in atrial fibrillation. Progress in Biophysics and Molecular Biology, 144, pp. 128-138. doi:10.1016/j.pbiomolbio.2018.06.009.
Staudacher I, et al. Cardiac K2P13.1 (THIK-1) Two-pore-domain K+ Channels: Pharmacological Regulation and Remodeling in Atrial Fibrillation. Prog Biophys Mol Biol. 2019;144:128-138. PubMed PMID: 31182191.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cardiac K2P13.1 (THIK-1) two-pore-domain K+ channels: Pharmacological regulation and remodeling in atrial fibrillation. AU - Staudacher,Ingo, AU - Seehausen,Sebastian, AU - Illg,Claudius, AU - Lugenbiel,Patrick, AU - Schweizer,Patrick A, AU - Katus,Hugo A, AU - Thomas,Dierk, Y1 - 2018/07/06/ PY - 2018/03/05/received PY - 2018/05/28/revised PY - 2018/06/25/accepted PY - 2019/6/12/entrez PY - 2019/6/12/pubmed PY - 2019/6/12/medline KW - Arrhythmia KW - Atrial fibrillation KW - Electrical remodeling KW - Electrophysiology KW - K(2P)13.1 channel SP - 128 EP - 138 JF - Progress in biophysics and molecular biology JO - Prog. Biophys. Mol. Biol. VL - 144 N2 - Cardiac two-pore-domain potassium (K2P) channels have been proposed as novel antiarrhythmic targets. K2P13.1 (THIK-1) channels are expressed in the human heart, and atrial K2P13.1 levels are reduced in patients with atrial fibrillation (AF) or heart failure. The first objective of this study was to investigate acute effects of antiarrhythmic drugs on human K2P13.1 currents. Second, we assessed atrial K2P13.1 remodeling in AF pigs to validate the porcine model for future translational evaluation of K2P13.1-based antiarrhythmic concepts. K2P13.1 protein expression was studied in domestic pigs during AF induced by atrial burst pacing. AF was associated with 66% reduction of K2P13.1 levels in the right atrium at 21-day follow-up. Voltage clamp electrophysiology was employed to elucidate human K2P13.1 channel pharmacology in Xenopus oocytes. Propafenone (-26%; 100 μM), mexiletine (-75%; 1.5 mM), propranolol (-38%; 200 μM), and lidocaine (-59%; 100 μM) significantly inhibited K2P13.1 currents. By contrast, K2P13.1 channels were not markedly affected by quinidine, carvedilol, metoprolol, amiodarone and verapamil. Concentration-dependent K2P13.1 blockade by mexiletine occurred rapidly with membrane depolarization and was frequency-independent. Mexiletine reduced K2P13.1 open rectification properties and shifted current-voltage relationships towards more negative potentials. In conclusion, atrial expression and AF-associated downregulation of K2P13.1 channels in a porcine model resemble human findings and support a general role for K2P13.1 in AF pathophysiology. K2P13.1 current sensitivity to antiarrhythmic drugs provides a starting point for further development of an emerging antiarrhythmic paradigm. SN - 1873-1732 UR - https://www.unboundmedicine.com/medline/citation/31182191/Cardiac_K2P13.1_(THIK-1)_two-pore-domain_K+_channels:_Pharmacological_regulation_and_remodeling_in_atrial_fibrillation L2 - https://linkinghub.elsevier.com/retrieve/pii/S0079-6107(18)30067-1 DB - PRIME DP - Unbound Medicine ER -