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EMBO Mol Med. 2017 Apr;9(4):403-414. doi: 10.15252/emmm.201606690.

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

Author information

1
Institute of Physiology and Pathophysiology, Vegetative Physiology, Philipps-University of Marburg, Marburg, Germany decher@staff.uni-marburg.de.
2
Institute of Physiology and Pathophysiology, Vegetative Physiology, Philipps-University of Marburg, Marburg, Germany.
3
Department of Cardiovascular Medicine, Institute for Genetics of Heart Diseases (IfGH), University Hospital Münster, Münster, Germany.
4
Institute of Physiology, Christian-Albrechts-University of Kiel, Kiel, Germany.
5
Institute for Experimental Cardiovascular Medicine, University Heart Center Freiburg - Bad Krozingen, Medical Center - University of Freiburg, Freiburg, Germany.
6
Faculty of Medicine, University of Freiburg, Freiburg, Germany.
7
Center for Bioinformatics and Molecular Simulation, University of Talca, Talca, Chile.
8
Institute of Pharmacology and Clinical Pharmacy, Biochemical and Pharmacological Center (BPC) Philipps-University of Marburg, Marburg, Germany.
9
Molecular Cardiology, University Hospital Ulm, Ulm, Germany.

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 K2P potassium channel TREK-1 (KCNK2 or 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 K2P channel stretch-activation and the role of TREK-1 in mechano-electrical feedback in the heart.

KEYWORDS:

RVOT ; K2P; TREK‐1; arrhythmia; two‐pore domain K+ channel

PMID:
28242754
PMCID:
PMC5376757
DOI:
10.15252/emmm.201606690
[Indexed for MEDLINE]
Free PMC Article

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