Modulation of I(Kr) inactivation by mutation N588K in KCNH2: a link to arrhythmogenesis in short QT syndrome.
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.


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 I(Kr) 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.
Cordeiro
J M
JM
Department of Experimental Cardiology, Masonic Medical Research Laboratory, 2150 Bleecker Street, Utica, NY 13501, USA. jcordeiro@mmrl.edu
Brugada
R
R
Wu
Y S
YS
Hong
K
K
Dumaine
R
R
D000200:Action Potentials; D002460:Cell Line; D016757:Death, Sudden, Cardiac / Q000209:etiology*; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D015640:Ion Channel Gating; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D032383:Myocytes, Cardiac / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics / Q000378:metabolism; D011690:Purkinje Fibers / Q000378:metabolism*; D014162:Transfection / Q000379:methods; D014693:Ventricular Fibrillation / Q000235:genetics* / Q000378:metabolism
D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C489619:KCNE2 protein, human; C000606913:KCNH2 protein, human; D024642:Potassium Channels, Voltage-Gated