Knock-Out of the Potassium Channel TASK-1 Leads to a Prolonged QT Interval and a Disturbed QRS Complex

Abstract

Background/Aims: The aim of the study was to characterize the whole cell current of the two-pore domain potassium channel TASK-1 (K2P3) in mouse ventricular cardiomyocytes (I_TASK-1) and to analyze the cardiac phenotype of the TASK-1^-/- mice. Methods and Results: We have quantified the ventricular I_TASK-1 current using the blocker A293 and TASK-1^-/- mice. Surface electrocardiogram recordings of TASK-1^-/- mice showed a prolonged QTc interval and a broadened QRS complex. The differences in electrocardiograms between wild type and TASK-1^-/- mice disappeared during sympathetic stimulation of the animals. Quantitative RT-PCR, patch clamp recordings and measurements of hemodynamic performance of TASK-1^-/- mice revealed no major compensatory changes in ion channel transcription. Action potential recordings of TASK-1^-/- mouse cardiomyocytes indicated that I_TASK-1 modulates action potential duration. Our in vivo electrophysiological studies showed that isoflurane, which activates TASK-1, slowed heart rate and atrioventricular conduction of wild-type but not of TASK-1^-/- mice. Conclusion: The results of an invasive electrophysiological catheter protocol in combination with the observed QRS time prolongation in the surface electrocardiogram point towards a regulatory role of TASK-1 in the cardiac conduction system.

TASK-1 Channels May Modulate Action Potential Duration of Human Atrial Cardiomyocytes

“…Due to a lack of specific TASK-1 blockers, it was in the past not possible to isolate native atrial I TASK-1 in human heart. We have recently used the TASK-1 specific blocker A293 to isolate I TASK-1 in rat and mouse ventricular cardiomyocytes [6,7]. In the present study we show that in the human heart TASK-1 is specifically expressed in the atrium and we provide a quantitative description of I TASK-1 in human atrial myocytes.…”

Ability to Induce Atrial Fibrillation in the Peri-operative Period Is Associated with Phosphorylation-dependent Inhibition of TWIK Protein-related Acid-sensitive Potassium Channel 1 (TASK-1)

“…Decreased TASK-1 current could promote the initiation or maintenance of an arrhythmia by prolonging the action potential duration and causing after depolarizations, spurring ectopic beats and inhomogeneity of refractoriness that can lead to re-entry. These phenomena have been studied extensively in the ventricle, including in the TASK-1 knock-out mouse (12,13) and in mouse and rat ventricular myocytes after TASK-1 inhibition (6,23). However, the properties of the ventricular action potential differ greatly from the atrial action potential, and thus an alternative mechanism may be at work in this model of peri-op AF.…”

“…TASK-1-deficient transgenic mice have a mild cardiac phenotype, with a faster resting heart rate, a longer rate-corrected QT interval, and a broader QRS complex (12,13) than wildtype mice, suggesting a role for TASK-1 in excitability and in ventricular repolarization in rodents. In human atrial myocytes, TASK-1 inhibition leads to action potential prolongation (14), indicating that TASK-1 may have an important function in the human atrial action potential.…”

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

“…Twopore-domain potassium channel (K 2p ) genes such as KCNK17 (encoding K 2p 17.1, also known as TASK-4 and TALK-2) are known to be robustly expressed in myriad tissues, including cardiac and central nervous system, where they traditionally have been thought to regulate background cell excitability as leak channels (28,29). However, a wealth of transgenic animal studies support the notion that TASK family K 2p channels also strongly contribute to cardiac repolarization (30)(31)(32). Recently, Friedrich et al (27) used exome sequencing to identify a gain-of-function mutation in KCNK17 that in tandem with an SCN5A mutation underpinned the molecular mechanism of a severely affected arrhythmia phenotype.…”