title: Cardiac expression and atrial fibrillation-associated remodeling of K₂p2.1 (TREK-1) K⁺ channels in a porcine model.
abstract: OBJECTIVE
  Effective management of atrial fibrillation (AF) often remains an unmet need. Cardiac two-pore-domain K(+) (K2P) channels are implicated in action potential regulation, and their inhibition has been proposed as a novel antiarrhythmic strategy. K2P2.1 (TREK-1) channels are expressed in the human heart. This study was designed to identify and functionally express porcine K2P2.1 channels. In addition, we sought to analyze cardiac expression and AF-associated K2P2.1 remodeling in a clinically relevant porcine AF model.
  
  
  METHODS
  Three pK2P2.1 isoforms were identified and amplified. Currents were recorded using voltage clamp electrophysiology in the Xenopus oocyte expression system. K2P2.1 remodeling was studied by quantitative real time PCR and Western blot in domestic pigs during AF induced by atrial burst pacing.
  
  
  RESULTS
  Human and porcine K2P2.1 proteins share 99% identity. Residues involved in phosphorylation or glycosylation are conserved. Porcine K2P2.1 channels carried outwardly rectifying K(+) currents similar to their human counterparts. In pigs, K2P2.1 was expressed ubiquitously in the heart with predominance in the atrial tissue. AF was associated with time-dependent reduction of K2P2.1 protein in the RA by 70% (7 days of AF) and 80% (21 days of AF) compared to control animals in sinus rhythm. K2P2.1 expression in the left atrium, AV node, and ventricles was not affected by AF.
  
  
  CONCLUSIONS
  Similarities between porcine and human K2P2.1 channels indicate that the pig may represent a valid model for mechanistic and preclinical studies. AF-related atrial K2P2.1 remodeling has potential implications for arrhythmia maintenance and antiarrhythmic therapy.
authors.affiliation: Department of Cardiology, Medical University Hospital, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany.
authors.forename: Constanze
authors.initials: C
authors.lastname: Schmidt
authors.affiliation: Department of Cardiology, Medical University Hospital, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Wiedmann
authors.affiliation: Institute of Nanotechnology, Karlsruhe Institute of Technology, P.O. Box 3640, D-76021 Karlsruhe, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Tristram
authors.affiliation: Institute of Nanotechnology, Karlsruhe Institute of Technology, P.O. Box 3640, D-76021 Karlsruhe, Germany.
authors.forename: Priya
authors.initials: P
authors.lastname: Anand
authors.affiliation: Institute of Nanotechnology, Karlsruhe Institute of Technology, P.O. Box 3640, D-76021 Karlsruhe, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wenzel
authors.affiliation: Department of Cardiology, Medical University Hospital, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Lugenbiel
authors.affiliation: Department of Cardiology, Medical University Hospital, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Schweizer
authors.affiliation: Department of Cardiology, Medical University Hospital, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany.
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.affiliation: Department of Cardiology, Medical University Hospital, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany. Electronic address: dierk.thomas@med.uni-heidelberg.de.
authors.forename: Dierk
authors.initials: D
authors.lastname: Thomas
mesh_terms: D000818:Animals; D001281:Atrial Fibrillation / Q000503:physiopathology*; D015153:Blotting, Western; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D006031:Glycosylation; D006325:Heart Atria / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D009865:Oocytes; D018408:Patch-Clamp Techniques; D010766:Phosphorylation; D024683:Potassium Channels, Tandem Pore Domain / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D013045:Species Specificity; D013552:Swine; D013997:Time Factors; D014982:Xenopus laevis
chemical_list: D024683:Potassium Channels, Tandem Pore Domain; C103742:potassium channel protein TREK-1
keywords: Atrial fibrillation; Background potassium current; Cardiac action potential; Electrical remodeling; K(2P) channel; Membrane potential