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 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.

Physiological genomics identifies genetic modifiers of long QT syndrome type 2 severity

“…Furthermore, work by Schmidt et al (33) showed that pharmacological inhibition of a K 2p (TASK-1) is a novel potential pharmacological strategy for treatment of chronic atrial fibrillation. Additionally, Decher et al identified a mechanism in a patient whereby increased sodium permeability through a K 2p (TREK-1) predisposed the individual to right ventricular outflow tract ventricular tachycardia (34). Finally, recent work from our laboratory corroborates the notion that K 2p channels are more than simply background leak channels, acting as active participants in ventricular repolarization (35).…”

The VAMP‐associated protein VAPB is required for cardiac and neuronal pacemaker channel function

“…Statistics were performed as previously described (29). Briefly, every dataset for wild-type and each mutant and for every current/kinetical feature analyzed were tested with a Shapiro-Wilk test for normality.…”

Ventricular tachycardia in the absence of structural heart disease

“…Some are terminated by Valsalva manoeuvre (50% in one study),12 likely through release of acetylcholine (decreases cAMP (cyclic AMP) concentrations via muscarinic cholinergic receptors) 9 13. Evidence for a somatic mutation increasing sensitivity to sympathetic stimulation of the focus has been reported 14. However, adenosine insensitivity and focal structural abnormalities on cardiac MRI have been reported in some individuals, suggesting that small re-entry circuits or abnormal automaticity may sometimes be a cause 9 15.…”