Differential Expression of hERG1 Channel Isoforms Reproduces Properties of Native IKr and Modulates Cardiac Action Potential Characteristics

Arnold Schwartz,Anders Peter Larsen,Søren-Peter Olesen

doi:10.1371/journal.pone.0009021

Arnold Schwartz, Anders Peter Larsen + Show 1 more

Open Access

https://doi.org/10.1371/journal.pone.0009021

Copy DOI

Abstract

BackgroundThe repolarizing cardiac rapid delayed rectifier current, I Kr, is composed of ERG1 channels. It has been suggested that two isoforms of the ERG1 protein, ERG1a and ERG1b, both contribute to I Kr. Marked heterogeneity in the kinetic properties of native I Kr has been described. We hypothesized that the heterogeneity of native I Kr can be reproduced by differential expression of ERG1a and ERG1b isoforms. Furthermore, the functional consequences of differential expression of ERG1 isoforms were explored as a potential mechanism underlying native heterogeneity of action potential duration (APD) and restitution.Methodology/Principal FindingsThe results show that the heterogeneity of native I Kr can be reproduced in heterologous expression systems by differential expression of ERG1a and ERG1b isoforms. Characterization of the macroscopic kinetics of ERG1 currents demonstrated that these were dependent on the relative abundance of ERG1a and ERG1b. Furthermore, we used a computational model of the ventricular cardiomyocyte to show that both APD and the slope of the restitution curve may be modulated by varying the relative abundance of ERG1a and ERG1b. As the relative abundance of ERG1b was increased, APD was gradually shortened and the slope of the restitution curve was decreased.Conclusions/SignificanceOur results show that differential expression of ERG1 isoforms may explain regional heterogeneity of I Kr kinetics. The data demonstrate that subunit dependent changes in channel kinetics are important for the functional properties of ERG1 currents and hence I Kr. Importantly, our results suggest that regional differences in the relative abundance of ERG1 isoforms may represent a potential mechanism underlying the heterogeneity of both APD and APD restitution observed in mammalian hearts.

Highlights

The molecular correlate of the cardiac rapid delayed rectifier current, IKr, is the ERG1 (Kv11.1) ion channel [1,2]
We find that the characteristics of native IKr transients can be reproduced in heterologous expression systems by differential expression of hERG1a and hERG1b isoforms
In order to address whether differential expression of hERG1a and hERG1b was able to modulate the ‘peak potential’, i.e. the potential where the current peaks during a repolarizing voltage ramp, we transfected HEK293 cells with either hERG1a, hERG1b or both channel subunits

Summary

Introduction

The molecular correlate of the cardiac rapid delayed rectifier current, IKr, is the ERG1 (Kv11.1) ion channel [1,2]. Two isoforms of ERG1, ERG1a and ERG1b, have been detected on the protein level in both rat, canine and human cardiac tissue [5]. A mutation in the unique N-terminus of hERG1b was discovered in a patient with long QT syndrome [9] highlighting the importance of this isoform in cardiac repolarization. It has been suggested that two isoforms of the ERG1 protein, ERG1a and ERG1b, both contribute to IKr. Marked heterogeneity in the kinetic properties of native IKr has been described. We hypothesized that the heterogeneity of native IKr can be reproduced by differential expression of ERG1a and ERG1b isoforms. The functional consequences of differential expression of ERG1 isoforms were explored as a potential mechanism underlying native heterogeneity of action potential duration (APD) and restitution

Methods

Results

Conclusion