Action potential clamp and chloroquine sensitivity of mutant Kir2.1 channels responsible for variant 3 short QT syndrome.

Journal of Molecular and Cellular Cardiology
Aziza El HarchiJules C Hancox

Abstract

Recently identified genetic forms of short QT syndrome (SQTS) are associated with an increased risk of arrhythmia and sudden death. The SQT3 variant is associated with an amino-acid substitution (D172N) in the KCNJ2-encoded Kir2.1 K+ channel. In this study, whole-cell action potential (AP) clamp recording from transiently transfected Chinese Hamster Ovary cells at 37 degrees C showed marked augmentation of outward Kir2.1 current through D172N channels, associated with right-ward voltage-shifts of peak repolarizing current during both ventricular and atrial AP commands. Peak outward current elicited by ventricular AP commands was inhibited by chloroquine with an IC50 of 2.45 microM for wild-type (WT) Kir2.1, of 3.30 microM for D172N-Kir2.1 alone and of 3.11 microM for co-expressed WT and D172N (P>0.05 for all). These findings establish chloroquine as an effective inhibitor of SQT3 mutant Kir2.1 channels.

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Citations

Aug 28, 2009·Cellular Physiology and Biochemistry : International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology·Angelica Lopez-IzquierdoJose A Sanchez-Chapula
Feb 7, 2012·Cardiovascular Research·Ismail AdeniranHenggui Zhang
Feb 29, 2016·Pharmacological Reports : PR·Aldo A Rodríguez-MenchacaJosé A Sánchez-Chapula
Feb 8, 2011·Heart Rhythm : the Official Journal of the Heart Rhythm Society·Marcel A G van der Heyden, José A Sánchez-Chapula
Jul 31, 2013·Journal of Cardiovascular Electrophysiology·Hugues Abriel, Jean-Sébastien Rougier
Oct 13, 2011·Journal of Molecular and Cellular Cardiology·Aziza El HarchiJules C Hancox
Aug 20, 2016·Channels·Shuxi RenHailong An
Feb 22, 2017·European Journal of Pharmacology·Leticia G Marmolejo-MurilloTania Ferrer
Jun 14, 2017·PLoS Computational Biology·Dominic G WhittakerHenggui Zhang
Jan 2, 2018·Oncotarget·Cunjin LuoHenggui Zhang
Apr 1, 2020·Cardiovascular Research·Lia CrottiMichael C Sanguinetti
Jun 9, 2017·Biomedical Engineering Online·Cunjin LuoHenggui Zhang
Feb 26, 2020·Medical & Biological Engineering & Computing·Aulia Khamas HeikhmakhtiarKi Moo Lim
Jun 23, 2020·International Journal of Antimicrobial Agents·Kanigula Mubagwa
Sep 14, 2021·Europace : European Pacing, Arrhythmias, and Cardiac Electrophysiology : Journal of the Working Groups on Cardiac Pacing, Arrhythmias, and Cardiac Cellular Electrophysiology of the European Society of Cardiology·Xuehui FanIbrahim El-Battrawy

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Methods Mentioned

BETA
transfection

Software Mentioned

Graphpad
Prism
WinWCP

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