Inhibitory phosphorylation of TASK‐1 is associated with atrial fibrillation

Abstract

Activation of the platelet‐activating factor (PAF) receptor leads to inhibition of TASK‐1, a two pore‐domain potassium channel. PAF‐induced TASK‐1 inhibition requires the activity of PKCε and causes repolarization abnormalities in isolated murine ventricular myocytes. We have previously shown that TASK‐1 current is absent from atrial myocytes derived from humans suffering from atrial fibrillation (AF). We now show that AF‐associated loss of TASK‐1 current occurs in spite of significantly higher levels of channel protein expression in AF atrium as compared to atrial tissue from patients in normal sinus rhythm, suggesting regulation by post‐translational modification. TASK‐1 current was restored in atrial myocytes by PP2A treatment, showing that inhibition in AF was phosphorylation‐dependent. We have made a construct of human TASK‐1 carboxy‐terminus fused to glutathione‐S‐transferase and made site‐directed mutants of potential PKC sites. Kinase reactions of these constructs with PKCε identified the phosphorylation site as T383, a result that was confirmed by LC‐MS/MS analysis. Similar mutations in the full length channel abrogated the ability of PAF to inhibit TASK‐1 current in whole cell patch clamp studies. These data provide an exciting new marker, and possible therapeutic target, for AF, the most common human arrhythmia.Supported by NIH grants 5R01HL070105‐04, 5TL1RR024158‐02 and Servier