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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

100%

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.

Action potential clamp and mefloquine sensitivity of recombinant IKs' channels incorporating the V307L KCNQ1 mutation

67%

El Harchi A., Mcpate M. J., Zhang Y. H., Zhang H., Hancox J. C.

Journal of Physiology and Pharmacology

2010

tom 61

nr 2

The slow delayed rectifier potassium current, 'IKs', contributes to repolarisation of cardiac ventricular action potentials and thereby to the duration of the QT interval of the electrocardiogram. Mutations to IKs channel subunits occur in clinically significant cardiac repolarisation disorders. The short QT syndrome (SQTS) is associated with accelerated ventricular repolarisation and with an increased risk of arrhythmia and sudden death. The SQT2 variant of the SQTS has been linked to a gain-of-function amino-acid substitution (V307L) in the KCNQ1-encoded IKs channel -subunit. This study reports the first action potential (AP) voltage-clamp comparison between wild-type (WT) and V307L KCNQ1 (co-expressed with KCNE1 to recapitulate IKs) and identifies an effective pharmacological inhibitor of recombinant 'IKs' channels incorporating the V307L KCNQ1 mutation. Perforated-patch voltage-clamp recordings at 37°C of whole-cell current carried by co-expressed KCNQ1 and KCNE1 showed a marked (-36 mV) shift in half-maximal activation for V307L compared to WT KCNQ1; a significant slowing of current deactivation was also observed. Under AP clamp, peak repolarising current was significantly augmented for V307L KCNQ1 compared to WT KCNQ1 for both ventricular and atrial AP commands, consistent with an ability of the V307L mutation to increase repolarising IKs in both regions. The quinoline agent mefloquine inhibited WT KCNQ1+KCNE1 with an IC50 of 3.4 µM compared to 3.3 µM for V307L KCNQ1+KCNE1 (P >0.05). This establishes mefloquine as an effective inhibitor of recombinant 'IKs' channels incorporating this SQT2 KCNQ1 mutation.

Modulation by testosterone of an endogenous hERG potassium channel current

67%

Ridley J. M., Shuba Y. M., James A. F., Hancox J. C.

Journal of Physiology and Pharmacology

2008

tom 59

nr 3

395-407

hERG (human ether-a-go-go-related gene) potassium (K+) channels are expressed in a range of tissue types including neuroblastoma cells and the heart, in which hERG K+ current is important for action potential repolarization. Whilst gender differences in cardiac repolarization and the QT interval of the cardiac electrocardiogram are well-established, comparatively little is known about regulation of hERG channels by sex hormones. In this study, whole-cell patch-clamp recordings were made at 37 °C from SH-SY5Y human neuroblastoma cells to investigate modulation of endogenous hERG K+ channel current (IhERG) by testosterone. Acutely applied testosterone at a physiologically relevant concentration (10 nM) produced a modest (~13-15 %) increase in IhERG amplitude, whilst a high concentration (1 µM) slightly decreased IhERG. The stimulatory effect of testosterone was inhibited by the androgen receptor antagonist flutamide (10 µM) and the PI-3 kinase inhibitor wortmannin (1 µM). Chronic (24 h) application of testosterone also augmented IhERG via flutamide-sensitive receptor activation, without modulation of the current's voltage-dependence. These results demonstrate for the first time that testosterone can stimulate hERG K+ channels via activation of classical androgen receptors and implicate PI-3 kinase in the acute response.

Ograniczanie wyników

3 Journal of Physiology and Pharmacology

3 Hancox J. C.

2 Zhang H.

1 Adeniran I.

1 Cordeiro J. M.

1 El Harchi A.

1 James A. F.

1 McPate M. J.

1 Mcpate M. J.

1 Ridley J. M.

1 Shuba Y. M.

1 Witchel H. J.

1 Zhang Y. H.

1 2010

1 2009

1 2008

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

Action potential clamp and mefloquine sensitivity of recombinant IKs' channels incorporating the V307L KCNQ1 mutation

Modulation by testosterone of an endogenous hERG potassium channel current