Sodium permeable and "hypersensitive" TREK-1 channels cause ventricular tachycardia.

Gunnar Seemann, Eric Schulze-Bahr, Thomas Baukrowitz, Wendy González, Steffen Just, Peter Kohl, Jens Kockskämper, Daniel Bustos, Rémi Peyronnet, Birgit Stallmeyer, Susanne Rinné, Aytug K Kiper, Marcus Schewe, Corinna Friedrich, Beatriz Ortiz-Bonnin, Niels Decher, Sven Zumhagen

Journal: EMBO molecular medicine 2017;9(4):403-414

PMID: 28242754

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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 K potassium channel TREK-1 ( or K2.1). 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 K channel stretch-activation and the role of TREK-1 in mechano-electrical feedback in the heart.

Address: Institute of Physiology and Pathophysiology, Vegetative Physiology, Philipps-University of Marburg, Marburg, Germany [email protected].; Institute of Physiology and Pathophysiology, Vegetative Physiology, Philipps-University of Marburg, Marburg, Germany.; Department of Cardiovascular Medicine, Institute for Genetics of Heart Diseases (IfGH), University Hospital Münster, Münster, Germany.; Institute of Physiology, Christian-Albrechts-University of Kiel, Kiel, Germany.; 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.; Center for Bioinformatics and Molecular Simulation, University of Talca, Talca, Chile.; Institute of Pharmacology and Clinical Pharmacy, Biochemical and Pharmacological Center (BPC) Philipps-University of Marburg, Marburg, Germany.; Molecular Cardiology, University Hospital Ulm, Ulm, Germany.

DOI: 10.15252/emmm.201606690

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MeSH Terms: Humans, Middle Aged, Mutant Proteins, Potassium Channels, Tandem Pore Domain, Sodium, Tachycardia, Ventricular