TASK-1 current is inhibited by phosphorylation during human and canine chronic atrial fibrillation

Abstract

Atrial fibrillation (AF) is a common arrhythmia with significant morbidities and only partially adequate therapeutic options. AF is associated with atrial remodeling processes, including changes in the expression and function of ion channels and signaling pathways. TWIK protein-related acid-sensitive K+ channel (TASK)-1, a two-pore domain K+ channel, has been shown to contribute to action potential repolarization as well as to the maintenance of resting membrane potential in isolated myocytes, and TASK-1 inhibition has been associated with the induction of perioperative AF. However, the role of TASK-1 in chronic AF is unknown. The present study investigated the function, expression, and phosphorylation of TASK-1 in chronic AF in atrial tissue from chronically paced canines and in human subjects. TASK-1 current was present in atrial myocytes isolated from human and canine hearts in normal sinus rhythm but was absent in myocytes from humans with AF and in canines after the induction of AF by chronic tachypacing. The addition of phosphatase to the patch pipette rescued TASK-1 current from myocytes isolated from AF hearts, indicating that the change in current is phosphorylation dependent. Western blot analysis showed that total TASK-1 protein levels either did not change or increased slightly in AF, despite the absence of current. In studies of perioperative AF, we have shown that phosphorylation of TASK-1 at Thr383 inhibits the channel. However, phosphorylation at this site was unchanged in atrial tissue from humans with AF or in canines with chronic pacing-induced AF. We conclude that phosphorylation-dependent inhibition of TASK-1 is associated with AF, but the phosphorylation site responsible for this inhibition remains to be identified.

Serine/Threonine Phosphatases in Atrial Fibrillation

“…Expression of K 2P 3.1 channels and functional I K2P were increased in cAF patients in our cohort, contributing significantly to AF-associated APD shortening [68]. By contrast, others have found reduced I K2P in a cohort of AF patients with mitral valve disease, which could be rescued by exogenous application of phosphatases [69], suggesting that abnormal regulation of K 2P channel phosphorylation may affect I K2P in certain patient populations. However, also for I K2P it is unknown whether this abnormal phosphorylation is due to reduced dephosphorylation and, if so, which phosphatases and anchoring proteins are involved.…”

Computational Modeling of Electrophysiology and Pharmacotherapy of Atrial Fibrillation: Recent Advances and Future Challenges

“…Some studies reported increased channel expression in cAF ( Barth et al, 2005 ; Schmidt et al, 2015 , 2017 ), while no change was found by others ( Ellinghaus et al, 2005 ; Gaborit et al, 2005 ). Similarly, functional measurements have shown both increased ( Schmidt et al, 2015 , 2017 ) and diminished ( Harleton et al, 2015 ) I K,2P amplitudes in cAF.…”

K2p3.1 protein is expressed as a transmural gradient across the rat left ventricular free wall

“…6,7 It also shows phosphorylation-dependent inhibition by protein kinase C 7 and inhibition by platelet activating factor. 6,7 It also shows phosphorylation-dependent inhibition by protein kinase C 7 and inhibition by platelet activating factor.…”

“…1 Channel functionality of K 2p 3.1 can also be modulated by several other factors: inhibition occurs during hypoxia, in response to α adrenergic 4 and endothelin-1 receptor stimulation 5 and in the presence of the endocannabinoid anandamide (or its stable analog methanandamide). 6,7 It also shows phosphorylation-dependent inhibition by protein kinase C 7 and inhibition by platelet activating factor. 8 In contrast, activation of K 2p 3.1 channels occurs in response to the key inhalational anesthetics halothane, sevoflurane, and isoflurane.…”