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

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_2P potassium channel TREK-1 (KCNK2 or K_2P2.1). 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_2P channel stretch-activation and the role of TREK-1 in mechano-electrical feedback in the heart.