Sodium permeable and “hypersensitive” TREK ‐1 channels cause ventricular tachycardia

• DOI: 10.15252/emmm.201606690
• Publication Date: 2017-02-28T01:10:30Z
• Authors: Niels Decher; Beatriz Ortiz‐Bonnin; Corinna Friedrich; Marcus Schewe; Aytug K Kiper; Susanne Rinné; Gunnar Seemann; Rémi Peyronnet; Sven Zumhagen; Daniel Bustos; Jens Kockskämper; Peter Kohl; Steffen Just; Wendy González; Thomas Baukrowitz; Birgit Stallmeyer; Eric Schulze‐Bahr
• Keywords: Medicine (General); K2P; Sodium; 610; 11 Medical And Health Sciences; RVOT; 06 Biological Sciences; QH426-470; Middle Aged; arrhythmia; R5-920; Potassium Channels, Tandem Pore Domain; Genetics; Tachycardia, Ventricular; TREK‐1; two‐pore domain K+ channel; Humans; Mutant Proteins; Research Articles

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.