KCNE2 modulation of Kv4.3 current and its potential role in fatal rhythm disorders

Received 20 August 2009; accepted 7 October 2009. published online 12 October 2009.

Background

The transient outward current Ito is of critical importance in regulating myocardial electrical properties during the very early phase of the action potential. The auxiliary β subunit KCNE2 recently was shown to modulate Ito.

Objective

The purpose of this study was to examine the contributions of KCNE2 and its two published variants (M54T, I57T) to Ito.

Methods

The functional interaction between Kv4.3 (α subunit of human Ito) and wild-type (WT), M54T, and I57T KCNE2, expressed in a heterologous cell line, was studied using patch-clamp techniques.

Results

Compared to expression of Kv4.3 alone, co-expression of WT KCNE2 significantly reduced peak current density, slowed the rate of inactivation, and caused a positive shift of voltage dependence of steady-state inactivation curve. These modifications rendered Kv4.3 channels more similar to native cardiac Ito. Both M54T and I57T variants significantly increased Ito current density and slowed the inactivation rate compared with WT KCNE2. Moreover, both variants accelerated the recovery from inactivation.

Conclusion

The study results suggest that KCNE2 plays a critical role in the normal function of the native Ito channel complex in human heart and that M54T and I57T variants lead to a gain of function of Ito, which may contribute to generating potential arrhythmogeneity and pathogenesis for inherited fatal rhythm disorders.

Keywords: Cardiac arrhythmia, M54T variation, I57T variation, KCNE2, Kv4.3, Sudden cardiac death

Abbreviations: CHO, Chinese hamster ovary, HERG, human ether-a-go-go related gene, WT, wild type

⁎ Pharmacology Department, Medical School of Xi'an Jiaotong University. Xi'an, Shaanxi, China

† Division of Cardiology, Department of Internal Medicine, National Cardiovascular Center, Suita, Japan

‡ Department of Physiology, Shiga University of Medical Science, Ohtsu, Japan

§ Department of Cardiovascular Medicine, Kyoto University of Graduate School of Medicine, Kyoto, Japan

¶ Department of Cardiovascular Medicine, Shiga University of Medical Science, Shiga, Japan

∥ Laboratory of Molecular Genetics, National Cardiovascular Center, Suita, Japan

# Department of Medicine (Cardiology), University of Southern California, Los Angeles, California

⁎⁎ Cardiovascular Institute, Hospital Clinic, University of Barcelona, Barcelona, Spain

†† Heart Rhythm Management Centre, Free University of Brussels (UZ Brussel) VUB, Brussels, Belgium

‡‡ School of Medicine, Cardiovascular Genetics Center, University of Girona, Girona, Spain

§§ Departments of Pediatrics, Baylor College of Medicine, Houston, Texas

¶¶ Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas

∥∥ Masonic Medical Research Laboratory, Utica, New York

Address reprint requests and correspondence: Dr. Minoru Horie, Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan

The first two authors contributed equally to the original concept and the authorship of this study. This study was supported by grants from the Ministry of Education, Culture, Sports, Science, Technology Leading Project for Biosimulation to Dr. Horie; Health Sciences Research grants (H18-Research on Human Genome-002) from the Ministry of Health, Labour and Welfare, Japan to Drs. Shimizu and Horie; the National Natural Science Foundation of China (Key Program, No.30930105; General Program, No. 30873058, 30770785) and the National Basic Research Program of China (973 Program, No. 2007CB512005) and CMB Distinguished Professorships Award (No. F510000/G16916404) to Dr. Zang; and National Institutes of Health Grant HL47678 and Free and Accepted Masons of New York State and Florida to Dr. Antzelevitch.

PII: S1547-5271(09)01156-4

doi:10.1016/j.hrthm.2009.10.012

13 of 33