A mechanism underlying compound-induced voltage shift in the current activation of hERG by antiarrhythmic agents

Kazuharu Furutani, Yuko Yamakawa, Atsushi Inanobe, Miki Iwata, Yuko Ohno, Yoshihisa Kurachi

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Nifekalant and azimilide, Class III antiarrhythmic agents, block the human ether-à-go-go-related gene K + (hERG) channel. However, when a depolarizing membrane potential is applied, they also increase the current at low potentials by shifting its activation curve towards hyperpolarizing voltages. This phenomenon is called 'facilitation'. In this study, we tried to address the mechanism underlying the facilitation by analyzing the effects of various compounds on hERG expressed in Xenopus oocytes. Like nifekalant, amiodarone, quinidine and carvedilol, but not by dofetilide, caused the current facilitation of hERG, suggesting that the facilitation is a common effect to a subset of hERG blockers. As the concentration of each compound was increased, the total hERG current was suppressed progressively, while the current at low potentials was augmented. Activation curves of the remaining hERG current in the facilitation condition could be described as the sum of two Boltzmann functions reflecting two populations of hERG currents having different activation curves. The voltage shift in the activation curve from control was constant for each compound even at different concentrations; -31mV in amiodarone, -27mV in nifekalant, -17mV in quinidine and -12mV in carvedilol. Therefore, the facilitation is based on the appearance of hERG whose voltage-dependence for the activation is shifted towards hyperpolarizing voltages.

Original languageEnglish (US)
Pages (from-to)141-146
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume415
Issue number1
DOIs
StatePublished - Nov 11 2011
Externally publishedYes

Fingerprint

Quinidine
Amiodarone
Chemical activation
Electric potential
Xenopus
Ether
Membrane Potentials
Oocytes
Genes
Population
nifekalant
Membranes
carvedilol
dofetilide
azimilide

Keywords

  • Activation gating
  • Antiarrhythmic agent
  • HERG
  • K channel
  • Pharmacology

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

A mechanism underlying compound-induced voltage shift in the current activation of hERG by antiarrhythmic agents. / Furutani, Kazuharu; Yamakawa, Yuko; Inanobe, Atsushi; Iwata, Miki; Ohno, Yuko; Kurachi, Yoshihisa.

In: Biochemical and Biophysical Research Communications, Vol. 415, No. 1, 11.11.2011, p. 141-146.

Research output: Contribution to journalArticle

Furutani, Kazuharu ; Yamakawa, Yuko ; Inanobe, Atsushi ; Iwata, Miki ; Ohno, Yuko ; Kurachi, Yoshihisa. / A mechanism underlying compound-induced voltage shift in the current activation of hERG by antiarrhythmic agents. In: Biochemical and Biophysical Research Communications. 2011 ; Vol. 415, No. 1. pp. 141-146.
@article{4bd5d87e6e8845049461d539504790c0,
title = "A mechanism underlying compound-induced voltage shift in the current activation of hERG by antiarrhythmic agents",
abstract = "Nifekalant and azimilide, Class III antiarrhythmic agents, block the human ether-{\`a}-go-go-related gene K + (hERG) channel. However, when a depolarizing membrane potential is applied, they also increase the current at low potentials by shifting its activation curve towards hyperpolarizing voltages. This phenomenon is called 'facilitation'. In this study, we tried to address the mechanism underlying the facilitation by analyzing the effects of various compounds on hERG expressed in Xenopus oocytes. Like nifekalant, amiodarone, quinidine and carvedilol, but not by dofetilide, caused the current facilitation of hERG, suggesting that the facilitation is a common effect to a subset of hERG blockers. As the concentration of each compound was increased, the total hERG current was suppressed progressively, while the current at low potentials was augmented. Activation curves of the remaining hERG current in the facilitation condition could be described as the sum of two Boltzmann functions reflecting two populations of hERG currents having different activation curves. The voltage shift in the activation curve from control was constant for each compound even at different concentrations; -31mV in amiodarone, -27mV in nifekalant, -17mV in quinidine and -12mV in carvedilol. Therefore, the facilitation is based on the appearance of hERG whose voltage-dependence for the activation is shifted towards hyperpolarizing voltages.",
keywords = "Activation gating, Antiarrhythmic agent, HERG, K channel, Pharmacology",
author = "Kazuharu Furutani and Yuko Yamakawa and Atsushi Inanobe and Miki Iwata and Yuko Ohno and Yoshihisa Kurachi",
year = "2011",
month = "11",
day = "11",
doi = "10.1016/j.bbrc.2011.10.034",
language = "English (US)",
volume = "415",
pages = "141--146",
journal = "Biochemical and Biophysical Research Communications",
issn = "0006-291X",
publisher = "Academic Press Inc.",
number = "1",

}

TY - JOUR

T1 - A mechanism underlying compound-induced voltage shift in the current activation of hERG by antiarrhythmic agents

AU - Furutani, Kazuharu

AU - Yamakawa, Yuko

AU - Inanobe, Atsushi

AU - Iwata, Miki

AU - Ohno, Yuko

AU - Kurachi, Yoshihisa

PY - 2011/11/11

Y1 - 2011/11/11

N2 - Nifekalant and azimilide, Class III antiarrhythmic agents, block the human ether-à-go-go-related gene K + (hERG) channel. However, when a depolarizing membrane potential is applied, they also increase the current at low potentials by shifting its activation curve towards hyperpolarizing voltages. This phenomenon is called 'facilitation'. In this study, we tried to address the mechanism underlying the facilitation by analyzing the effects of various compounds on hERG expressed in Xenopus oocytes. Like nifekalant, amiodarone, quinidine and carvedilol, but not by dofetilide, caused the current facilitation of hERG, suggesting that the facilitation is a common effect to a subset of hERG blockers. As the concentration of each compound was increased, the total hERG current was suppressed progressively, while the current at low potentials was augmented. Activation curves of the remaining hERG current in the facilitation condition could be described as the sum of two Boltzmann functions reflecting two populations of hERG currents having different activation curves. The voltage shift in the activation curve from control was constant for each compound even at different concentrations; -31mV in amiodarone, -27mV in nifekalant, -17mV in quinidine and -12mV in carvedilol. Therefore, the facilitation is based on the appearance of hERG whose voltage-dependence for the activation is shifted towards hyperpolarizing voltages.

AB - Nifekalant and azimilide, Class III antiarrhythmic agents, block the human ether-à-go-go-related gene K + (hERG) channel. However, when a depolarizing membrane potential is applied, they also increase the current at low potentials by shifting its activation curve towards hyperpolarizing voltages. This phenomenon is called 'facilitation'. In this study, we tried to address the mechanism underlying the facilitation by analyzing the effects of various compounds on hERG expressed in Xenopus oocytes. Like nifekalant, amiodarone, quinidine and carvedilol, but not by dofetilide, caused the current facilitation of hERG, suggesting that the facilitation is a common effect to a subset of hERG blockers. As the concentration of each compound was increased, the total hERG current was suppressed progressively, while the current at low potentials was augmented. Activation curves of the remaining hERG current in the facilitation condition could be described as the sum of two Boltzmann functions reflecting two populations of hERG currents having different activation curves. The voltage shift in the activation curve from control was constant for each compound even at different concentrations; -31mV in amiodarone, -27mV in nifekalant, -17mV in quinidine and -12mV in carvedilol. Therefore, the facilitation is based on the appearance of hERG whose voltage-dependence for the activation is shifted towards hyperpolarizing voltages.

KW - Activation gating

KW - Antiarrhythmic agent

KW - HERG

KW - K channel

KW - Pharmacology

UR - http://www.scopus.com/inward/record.url?scp=80755135422&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80755135422&partnerID=8YFLogxK

U2 - 10.1016/j.bbrc.2011.10.034

DO - 10.1016/j.bbrc.2011.10.034

M3 - Article

C2 - 22020101

AN - SCOPUS:80755135422

VL - 415

SP - 141

EP - 146

JO - Biochemical and Biophysical Research Communications

JF - Biochemical and Biophysical Research Communications

SN - 0006-291X

IS - 1

ER -