A key to potassium channel activation: Using drugs to activate potassium channels has the potential to treat conditions like epilepsy, heart arrhythmias, and pain. Schewe et al. report a class of negatively charged activators (NCAs) with a defined pharmacore that use a similar mechanism to activate many types of potassium channels. X-ray crystallography, functional analysis, and molecular dynamics simulations showed that the NCAs bind below the selectivity filter to open the filter gate and activate the channels. Targeting this NCA site might be exploited in rational drug design. Science , this issue p. 875

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 _2P 2.1). 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.

Analyzing a patient with progressive and severe cardiac conduction disorder combined with idiopathic ventricular fibrillation (IVF), we identified a splice site mutation in the sodium channel gene SCN5A . Due to the severe phenotype, we performed whole‐exome sequencing (WES) and identified an additional mutation in the KCNK17 gene encoding the K _2P potassium channel TASK‐4. The heterozygous change (c.262G>A) resulted in the p.Gly88Arg mutation in the first extracellular pore loop. Mutant TASK‐4 channels generated threefold increased currents, while surface expression was unchanged, indicating enhanced conductivity. When co‐expressed with wild‐type channels, the gain‐of‐function by G88R was conferred in a dominant‐active manner. We demonstrate that KCNK17 is strongly expressed in human Purkinje cells and that overexpression of G88R leads to a hyperpolarization and strong slowing of the upstroke velocity of spontaneously beating HL‐1 cells. Thus, we propose that a gain‐of‐function by TASK‐4 in the conduction system might aggravate slowed conductivity by the loss of sodium channel function. Moreover, WES supports a second hit‐hypothesis in severe arrhythmia cases and identified KCNK17 as a novel arrhythmia gene.