Work

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)

Year: 2012

Type: article

Abstract: Peri-operative atrial fibrillation (peri-op AF) is a common complication following thoracic surgery. This arrhythmia is thought to be triggered by an inflammatory response and can be reproduced in various animal models. Previous work has shown that the lipid inflammatory mediator, platelet-activating factor (PAF), synthesized by activated neutrophils, can induce atrial and ventricular arrhythmias as well as repolarization abnormalities in isolated ventricular myocytes. We have previously shown that carbamylated PAF-induced repolarization abnormalities result from the protein kinase C (PKC) ϵ-dependent phosphorylation of the two-pore domain potassium channel TASK-1. We now demonstrate that canine peri-op AF is associated with the phosphorylation-dependent loss of TASK-1 current. Further studies identified threonine 383 in the C terminus of human and canine TASK-1 as the phosphorylation site required for PAF-dependent inhibition of the channel. Using a novel phosphorylation site-specific antibody targeting the phosphorylated channel, we have determined that peri-op AF is associated with the loss of TASK-1 current and increased phosphorylation of TASK-1 at this site. Background: Peri-operative atrial fibrillation (AF) is a common complication of thoracic surgery linked to inflammation. Results: TASK-1 current is absent from atrial myocytes isolated from AF dogs. The inhibition is phosphorylation-dependent, and threonine 383 is a PKC target in this model. Conclusion: TASK-1 inhibition and phosphorylation are associated with peri-operative AF. Significance: TASK-1 inhibition and phosphorylation are markers of peri-operative AF and are potential therapeutic targets.

Source: Journal of Biological Chemistry

DOI: 10.1074/jbc.m112.404095