title: 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.
authors.affiliation: Department of Pharmacology, Columbia University Medical Center, New York, New York;
authors.forename: Erin
authors.initials: E
authors.lastname: Harleton
authors.affiliation: Department of Pharmacology, Columbia University Medical Center, New York, New York;
authors.forename: Alessandra
authors.initials: A
authors.lastname: Besana
authors.affiliation: Department of Pharmacology, Columbia University Medical Center, New York, New York;
authors.forename: Parag
authors.initials: P
authors.lastname: Chandra
authors.affiliation: Department of Pharmacology, Columbia University Medical Center, New York, New York;
authors.forename: Peter
authors.initials: P
authors.lastname: Danilo
authors.affiliation: Department of Pediatrics, Columbia University Medical Center, New York, New York.
authors.forename: Tove S
authors.initials: TS
authors.lastname: Rosen
authors.affiliation: Department of Pharmacology, Columbia University Medical Center, New York, New York; Department of Pediatrics, Columbia University Medical Center, New York, New York.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Rosen
authors.affiliation: Division of Cardiothoracic Surgery, Department of Surgery, Columbia University Medical Center, New York, New York; and.
authors.forename: Michael
authors.initials: M
authors.lastname: Argenziano
authors.affiliation: Department of Pharmacology, Columbia University Medical Center, New York, New York;
authors.forename: Richard B
authors.initials: RB
authors.lastname: Robinson
authors.affiliation: Department of Pharmacology, Columbia University Medical Center, New York, New York; sjf1@columbia.edu.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Feinmark
mesh_terms: D000200:Action Potentials; D000368:Aged; D000818:Animals; D001281:Atrial Fibrillation / Q000378:metabolism*; D016022:Case-Control Studies; D002478:Cells, Cultured; D004285:Dogs; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D024683:Potassium Channels, Tandem Pore Domain / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational
chemical_list: D009419:Nerve Tissue Proteins; D024683:Potassium Channels, Tandem Pore Domain; C420132:potassium channel subfamily K member 3
keywords: TWIK protein-related acid-sensitive potassium channel 1; atrial fibrillation; electrophysiology; two-pore domain potassium channel