Copyright © 2005, European Society of Cardiology
Modulation of IKr inactivation by mutation N588K in KCNH2: A link to arrhythmogenesis in short QT syndrome
aDepartment of Experimental Cardiology, Masonic Medical Research Laboratory, 2150 Bleecker Street, Utica, NY 13501, USA
bDepartment of Molecular Genetics, Masonic Medical Research Laboratory, Utica, NY 13501, USA
cDepartment of Molecular Biology, Masonic Medical Research Laboratory, Utica, NY 13501, USA
dDepartment of Physiology and Biophysics, Faculty of Medicine, University of Sherbrooke, 3001 12th Avenue N, Sherbrooke QC, Canada, J1H 5N4
* Corresponding authors. J.M. Cordeiro is to be contacted at Tel.: +1 315 735 2217x132; fax: +1 315 735 5648. R. Dumaine, Tel.: +1 819 564 5301; fax: +1 819 564 5399. Email address: jcordeiro{at}mmrl.edu robert.dumaine{at}usherbrooke.ca
Methods: We measured the characteristics of HERG current generated by wild-type (WT) KCNH2 and the N588K mutant channel expressed in mammalian TSA201 cells.
Results: Whole-cell patch-clamp recordings of WT HERG currents showed the usual rapid onset of inactivation (rectification) at potentials more positive than +10 mV. In contrast, N588K currents rectified at potentials over +80 mV. Over the physiological range of potentials, N588K currents do not inactivate. During an action potential clamp, WT currents displayed a "hump" like waveform with slow activation kinetics and a rapid increase during phase 3 repolarization. In contrast, N588K currents were proportional to the amplitude of the action potential and displayed a dome-like configuration and a much larger current during the initial phases in the ventricle. Purkinje cell action potentials display a more negative phase 2 repolarization than the ventricle and elicited much smaller WT and N588K currents of similar amplitudes.
Conclusions: Physiologically the N588K mutation abolishes rectification of HERG currents and specifically increases IKr in the ventricle with minimal effects on the Purkinje fiber action potential duration. Such preferential prolongation may explain the separation of the T and U waves observed in the ECG of SQTS patients and lead to re-excitation of the ventricle endocardium.
Objective: Short QT syndrome (SQTS) is characterized by ventricular arrhythmias and sudden death. One form of SQTS is caused by mutation N588K in human ether-a-go-go-related gene (HERG). In this study we sought to determine the potential role of N588K in arrhythmias.
KEYWORDS HERG; Short QT; Purkinje; Arrhythmias; Potassium channel
Time for primary review 17 days
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