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Comparative effects of the short QT N588K mutation at 37 degrees Celsius on hERG Kplus channel current during ventricular, purkinje fibre and atrial action potentials: an action potential clamp study

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McPate M. J., Zhang H., Adeniran I., Cordeiro J. M., Witchel H. J., Hancox J. C.

Journal of Physiology and Pharmacology

2009

tom 60

nr 1

23-41

The short QT syndrome (SQTS) is a cardiac repolarisation disorder characterised by abbreviated QT intervals on the electrocardiogram and by an increased risk of atrial and ventricular arrhythmias and sudden death. The SQT1 variant involves a gain-of-function mutation (N588K) that impairs inactivation of the hERG (human ether-a-go-go-related gene) potassium channel and, thereby, increases current mediated by the rapid delayed rectifier potassium current (IKr) in the heart. Here, the action potential voltage clamp (AP clamp) technique was applied to Chinese Hamster Ovary cells expressing wild-type or N588K-hERG at 37°C, to compare effects of the N588K mutation on hERG current (IhERG) during ventricular, atrial and Purkinje fibre APs. The N588K mutation altered the IhERG profile during each AP type; increased maximal repolarising current occurred earlier during AP repolarisation (with shifts of ~+60 mV, +30 mV and +15 mV respectively for ventricular, Purkinje fibre and atrial APs). Thus SQT1 may influence repolarising IhERG for each cell type, with AP clamp experiments and simulation data indicating the greatest effect during ventricular APs. Changes in the timing of outward IhERG transients elicited by premature stimuli following AP commands indicate that SQT1 may alter the protection that hERG provides cardiac tissue against premature arrhythmogenic stimuli.

Ograniczanie wyników

1 Journal of Physiology and Pharmacology

1 Adeniran I.

1 Cordeiro J. M.

1 Hancox J. C.

1 McPate M. J.

1 Witchel H. J.

1 Zhang H.

1 2009

Wyniki wyszukiwania

Comparative effects of the short QT N588K mutation at 37 degrees Celsius on hERG Kplus channel current during ventricular, purkinje fibre and atrial action potentials: an action potential clamp study