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Heart Rhythm. 2014 Oct;11(10):1798-805. doi: 10.1016/j.hrthm.2014.06.020. Epub 2014 Jun 18.

Cloning, functional characterization, and remodeling of K2P3.1 (TASK-1) potassium channels in a porcine model of atrial fibrillation and heart failure.

Author information

  • 1Department of Cardiology, University of Heidelberg, Heidelberg, Germany.
  • 2Institute of Nanotechnology, Karlsruhe Institute of Technology, Karlsruhe, Germany.
  • 3Department of Cardiology, University of Heidelberg, Heidelberg, Germany. Electronic address: dierk.thomas@med.uni-heidelberg.de.

Abstract

BACKGROUND:

Effective treatment of atrial fibrillation (AF) remains an unmet need. Human K2P3.1 (TASK-1) K(+) channels display atrial-specific expression and may serve as novel antiarrhythmic targets. In rodents, inhibition of K2P3.1 causes prolongation of action potentials and QT intervals. We used a porcine model to further elucidate the significance of K2P3.1 in large mammals.

OBJECTIVE:

The purpose of this study was to study porcine (p)K2P3.1 channel function and cardiac expression and to analyze pK2P3.1 remodeling in AF and heart failure (HF).

METHODS:

The porcine K2P3.1 ortholog was amplified and characterized using voltage-clamp electrophysiology. K2P3.1 mRNA expression and remodeling were studied in domestic pigs during AF and HF induced by atrial burst pacing.

RESULTS:

Porcine K2P3.1 cDNA encodes a channel protein with 97% identity to human K2P3.1. K(+) currents recorded from Xenopus oocytes expressing pK2P3.1 were functionally and pharmacologically similar to their human counterparts. In the pig, K2P3.1 mRNA was predominantly expressed in atrial tissue. AF and HF were associated with reduction of K2P3.1 mRNA levels by 85.1% (right atrium) and 77.0% (left atrium) at 21-day follow-up. In contrast, ventricular K2P3.1 expression was low and not significantly affected by AF/HF.

CONCLUSION:

Porcine K2P3.1 channels exhibit atrial expression and functional properties similar to their human orthologs, supporting a general role as antiarrhythmic drug targets. K2P3.1 down-regulation in AF with HF may indicate functional relevance of the channel that remains to be validated in prospective interventional studies.

Copyright © 2014 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

KEYWORDS:

Atrial fibrillation; Background potassium current; Cardiac action potential; Electrical remodeling; K(2P) channel

PMID:
24952150
[PubMed - indexed for MEDLINE]
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