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

Jie Wu, Wataru Shimizu, Wei Guang Ding, Seiko Ohno, Futoshi Toyoda, Hideki Itoh, Wei Jin Zang, Yoshihiro Miyamoto, Shiro Kamakura, Hiroshi Matsuura, Koonlawee Nademanee, Josep Brugada, Pedro Brugada, Ramon Brugada, Matteo Vatta, Jeffrey Towbin, Charles Antzelevitch, Minoru Horie

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)199-205
Number of pages7
JournalHeart Rhythm
Volume7
Issue number2
DOIs
StatePublished - Jan 1 2010
Externally publishedYes

Fingerprint

Patch-Clamp Techniques
Action Potentials
Cell Line

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Wu, J., Shimizu, W., Ding, W. G., Ohno, S., Toyoda, F., Itoh, H., ... Horie, M. (2010). KCNE2 modulation of Kv4.3 current and its potential role in fatal rhythm disorders. Heart Rhythm, 7(2), 199-205. https://doi.org/10.1016/j.hrthm.2009.10.012

KCNE2 modulation of Kv4.3 current and its potential role in fatal rhythm disorders. / Wu, Jie; Shimizu, Wataru; Ding, Wei Guang; Ohno, Seiko; Toyoda, Futoshi; Itoh, Hideki; Zang, Wei Jin; Miyamoto, Yoshihiro; Kamakura, Shiro; Matsuura, Hiroshi; Nademanee, Koonlawee; Brugada, Josep; Brugada, Pedro; Brugada, Ramon; Vatta, Matteo; Towbin, Jeffrey; Antzelevitch, Charles; Horie, Minoru.

In: Heart Rhythm, Vol. 7, No. 2, 01.01.2010, p. 199-205.

Research output: Contribution to journalArticle

Wu, J, Shimizu, W, Ding, WG, Ohno, S, Toyoda, F, Itoh, H, Zang, WJ, Miyamoto, Y, Kamakura, S, Matsuura, H, Nademanee, K, Brugada, J, Brugada, P, Brugada, R, Vatta, M, Towbin, J, Antzelevitch, C & Horie, M 2010, 'KCNE2 modulation of Kv4.3 current and its potential role in fatal rhythm disorders', Heart Rhythm, vol. 7, no. 2, pp. 199-205. https://doi.org/10.1016/j.hrthm.2009.10.012
Wu, Jie ; Shimizu, Wataru ; Ding, Wei Guang ; Ohno, Seiko ; Toyoda, Futoshi ; Itoh, Hideki ; Zang, Wei Jin ; Miyamoto, Yoshihiro ; Kamakura, Shiro ; Matsuura, Hiroshi ; Nademanee, Koonlawee ; Brugada, Josep ; Brugada, Pedro ; Brugada, Ramon ; Vatta, Matteo ; Towbin, Jeffrey ; Antzelevitch, Charles ; Horie, Minoru. / KCNE2 modulation of Kv4.3 current and its potential role in fatal rhythm disorders. In: Heart Rhythm. 2010 ; Vol. 7, No. 2. pp. 199-205.
@article{d4490a73d9074b25aec4bca97a566342,
title = "KCNE2 modulation of Kv4.3 current and its potential role in fatal rhythm disorders",
abstract = "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.",
author = "Jie Wu and Wataru Shimizu and Ding, {Wei Guang} and Seiko Ohno and Futoshi Toyoda and Hideki Itoh and Zang, {Wei Jin} and Yoshihiro Miyamoto and Shiro Kamakura and Hiroshi Matsuura and Koonlawee Nademanee and Josep Brugada and Pedro Brugada and Ramon Brugada and Matteo Vatta and Jeffrey Towbin and Charles Antzelevitch and Minoru Horie",
year = "2010",
month = "1",
day = "1",
doi = "10.1016/j.hrthm.2009.10.012",
language = "English (US)",
volume = "7",
pages = "199--205",
journal = "Heart Rhythm",
issn = "1547-5271",
publisher = "Elsevier",
number = "2",

}

TY - JOUR

T1 - KCNE2 modulation of Kv4.3 current and its potential role in fatal rhythm disorders

AU - Wu, Jie

AU - Shimizu, Wataru

AU - Ding, Wei Guang

AU - Ohno, Seiko

AU - Toyoda, Futoshi

AU - Itoh, Hideki

AU - Zang, Wei Jin

AU - Miyamoto, Yoshihiro

AU - Kamakura, Shiro

AU - Matsuura, Hiroshi

AU - Nademanee, Koonlawee

AU - Brugada, Josep

AU - Brugada, Pedro

AU - Brugada, Ramon

AU - Vatta, Matteo

AU - Towbin, Jeffrey

AU - Antzelevitch, Charles

AU - Horie, Minoru

PY - 2010/1/1

Y1 - 2010/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=74449089865&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=74449089865&partnerID=8YFLogxK

U2 - 10.1016/j.hrthm.2009.10.012

DO - 10.1016/j.hrthm.2009.10.012

M3 - Article

VL - 7

SP - 199

EP - 205

JO - Heart Rhythm

JF - Heart Rhythm

SN - 1547-5271

IS - 2

ER -