title: Sodium permeable and "hypersensitive" TREK-1 channels cause ventricular tachycardia.
abstract: In a patient with right ventricular outflow tract (RVOT) tachycardia, we identified a heterozygous point mutation in the selectivity filter of the stretch-activated K2Ppotassium channel TREK-1 (KCNK2or K2P2.1). This mutation introduces abnormal sodium permeability to TREK-1. In addition, mutant channels exhibit a hypersensitivity to stretch-activation, suggesting that the selectivity filter is directly involved in stretch-induced activation and desensitization. Increased sodium permeability and stretch-sensitivity of mutant TREK-1 channels may trigger arrhythmias in areas of the heart with high physical strain such as the RVOT We present a pharmacological strategy to rescue the selectivity defect of the TREK-1 pore. Our findings provide important insights for future studies of K2Pchannel stretch-activation and the role of TREK-1 in mechano-electrical feedback in the heart.
authors.affiliation: Institute of Physiology and Pathophysiology, Vegetative Physiology, Philipps-University of Marburg, Marburg, Germany decher@staff.uni-marburg.de.
authors.forename: Niels
authors.identifier: 0000-0001-8892-1231
authors.initials: N
authors.lastname: Decher
authors.affiliation: Institute of Physiology and Pathophysiology, Vegetative Physiology, Philipps-University of Marburg, Marburg, Germany.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Ortiz-Bonnin
authors.affiliation: Department of Cardiovascular Medicine, Institute for Genetics of Heart Diseases (IfGH), University Hospital Münster, Münster, Germany.
authors.forename: Corinna
authors.initials: C
authors.lastname: Friedrich
authors.affiliation: Institute of Physiology, Christian-Albrechts-University of Kiel, Kiel, Germany.
authors.forename: Marcus
authors.identifier: 0000-0002-6192-5651
authors.initials: M
authors.lastname: Schewe
authors.affiliation: Institute of Physiology and Pathophysiology, Vegetative Physiology, Philipps-University of Marburg, Marburg, Germany.
authors.forename: Aytug K
authors.initials: AK
authors.lastname: Kiper
authors.affiliation: Institute of Physiology and Pathophysiology, Vegetative Physiology, Philipps-University of Marburg, Marburg, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Rinné
authors.affiliation: Institute for Experimental Cardiovascular Medicine, University Heart Center Freiburg - Bad Krozingen, Medical Center - University of Freiburg, Freiburg, Germany.|Faculty of Medicine, University of Freiburg, Freiburg, Germany.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Seemann
authors.affiliation: Institute for Experimental Cardiovascular Medicine, University Heart Center Freiburg - Bad Krozingen, Medical Center - University of Freiburg, Freiburg, Germany.|Faculty of Medicine, University of Freiburg, Freiburg, Germany.
authors.forename: Rémi
authors.initials: R
authors.lastname: Peyronnet
authors.affiliation: Department of Cardiovascular Medicine, Institute for Genetics of Heart Diseases (IfGH), University Hospital Münster, Münster, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Zumhagen
authors.affiliation: Center for Bioinformatics and Molecular Simulation, University of Talca, Talca, Chile.
authors.forename: Daniel
authors.initials: D
authors.lastname: Bustos
authors.affiliation: Institute of Pharmacology and Clinical Pharmacy, Biochemical and Pharmacological Center (BPC) Philipps-University of Marburg, Marburg, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Kockskämper
authors.affiliation: Institute for Experimental Cardiovascular Medicine, University Heart Center Freiburg - Bad Krozingen, Medical Center - University of Freiburg, Freiburg, Germany.|Faculty of Medicine, University of Freiburg, Freiburg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Kohl
authors.affiliation: Molecular Cardiology, University Hospital Ulm, Ulm, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Just
authors.affiliation: Center for Bioinformatics and Molecular Simulation, University of Talca, Talca, Chile.
authors.forename: Wendy
authors.initials: W
authors.lastname: González
authors.affiliation: Institute of Physiology, Christian-Albrechts-University of Kiel, Kiel, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Baukrowitz
authors.affiliation: Department of Cardiovascular Medicine, Institute for Genetics of Heart Diseases (IfGH), University Hospital Münster, Münster, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Stallmeyer
authors.affiliation: Department of Cardiovascular Medicine, Institute for Genetics of Heart Diseases (IfGH), University Hospital Münster, Münster, Germany.
authors.forename: Eric
authors.initials: E
authors.lastname: Schulze-Bahr
mesh_terms: D006801:Humans; D008875:Middle Aged; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D024683:Potassium Channels, Tandem Pore Domain / Q000235:genetics* / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism*; D017180:Tachycardia, Ventricular / Q000235:genetics* / Q000503:physiopathology*
chemical_list: D050505:Mutant Proteins; D024683:Potassium Channels, Tandem Pore Domain; C103742:potassium channel protein TREK-1; D012964:Sodium
keywords: 
  RVOT
  ; K2P; TREK‐1; arrhythmia; two‐pore domain K+ channel