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

Background Effective treatment of atrial fibrillation (AF) remains an unmet need. Human K 2P 3.1 (TASK-1) K + channels display atrial-specific expression and may serve as novel antiarrhythmic targets. In rodents, inhibition of K 2P 3.1 causes prolongation of action potentials and QT intervals. We used a porcine model to further elucidate the significance of K 2P 3.1 in large mammals. Objective The purpose of this study was to study porcine (p)K 2P 3.1 channel function and cardiac expression and to analyze pK 2P 3.1 remodeling in AF and heart failure (HF). Methods The porcine K 2P 3.1 ortholog was amplified and characterized using voltage-clamp electrophysiology. K 2P 3.1 mRNA expression and remodeling were studied in domestic pigs during AF and HF induced by atrial burst pacing. Results Porcine K 2P 3.1 cDNA encodes a channel protein with 97% identity to human K 2P 3.1. K + currents recorded from Xenopus oocytes expressing pK 2P 3.1 were functionally and pharmacologically similar to their human counterparts. In the pig, K 2P 3.1 mRNA was predominantly expressed in atrial tissue. AF and HF were associated with reduction of K 2P 3.1 mRNA levels by 85.1% (right atrium) and 77.0% (left atrium) at 21-day follow-up. In contrast, ventricular K 2P 3.1 expression was low and not significantly affected by AF/HF. Conclusion Porcine K 2P 3.1 channels exhibit atrial expression and functional properties similar to their human orthologs, supporting a general role as antiarrhythmic drug targets. K 2P 3.1 down-regulation in AF with HF may indicate functional relevance of the channel that remains to be validated in prospective interventional studies.