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

McPate, M J, Zhang, H, Adeniran, I, Cordeiro, J M, Witchel, H J and Hancox, J C (2009) Comparative effects of the short QT N588K mutation at 37 degrees C on hERG K+ channel current during ventricular, Purkinje fibre and atrial action potentials: an action potential clamp study. Journal of Physiology and Pharmacology, 60 (1). pp. 23-41. ISSN 1899-1505

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Abstract

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 (I(Kr)) 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 degrees C, to compare effects of the N588K mutation on hERG current (I(hERG)) during ventricular, atrial and Purkinje fibre APs. The N588K mutation altered the I(hERG) 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 I(hERG) for each cell type, with AP clamp experiments and simulation data indicating the greatest effect during ventricular APs. Changes in the timing of outward I(hERG) transients elicited by premature stimuli following AP commands indicate that SQT1 may alter the protection that hERG provides cardiac tissue against premature arrhythmogenic stimuli

Item Type: Article
Keywords: arrhythmia, hERG, human ether-a-go-go-related gene, KCNH2, IKr; QT interval, short QT syndrome, rapid delayed rectifier, repolarisation disorder
Schools and Departments: Brighton and Sussex Medical School > Clinical and Laboratory Investigation
Subjects: R Medicine > RM Therapeutics. Pharmacology
R Medicine > RS Pharmacy and materia medica
Depositing User: Patricia Butler
Date Deposited: 13 Nov 2012 10:09
Last Modified: 13 Nov 2012 10:09
URI: http://sro.sussex.ac.uk/id/eprint/42061
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