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Action potential clamp characterization of the S631A hERG mutation associated with short QT syndrome
Andrew Butler1, Yihong Zhang1, Alan G Stuart2
1School of Physiology, Pharmacology and Neuroscience, Medical Sciences Building, University Walk, Bristol, United Kingdom.
Insights
The S631A hERG mutation accelerates cardiac repolarization, causing short QT syndrome. The antiarrhythmic drug quinidine effectively counteracts this accelerated repolarization, offering a potential treatment for patients with this mutation.
Area of Science:
- Cardiovascular Physiology
- Molecular Cardiology
- Ion Channel Function
Background:
- The hERG potassium channel is crucial for cardiac repolarization.
- Mutations in hERG are linked to Long and Short QT Syndromes, which can cause fatal arrhythmias.
- The S631A mutation, found in a Short QT Syndrome family, affects hERG channel inactivation.
Purpose of the Study:
- To characterize the functional impact of the S631A hERG mutation on cardiac action potentials.
- To investigate the effects of S631A on hERG current (IhERG) in different cardiac regions.
- To assess the efficacy of quinidine in counteracting the S631A mutation's effects.
Main Methods:
- Patch clamp recordings from hERG-expressing HEK 293 cells at 37°C.
- Characterization of IhERG under conventional voltage clamp and simulated cardiac action potential waveforms (ventricular, atrial, Purkinje fiber).
- Assessment of quinidine's effect on S631A IhERG.
Main Results:
- The S631A mutation caused a rightward shift in the IhERG current-voltage relationship.
- S631A resulted in augmented and earlier peaking IhERG during ventricular, atrial, and Purkinje fiber action potentials.
- Quinidine (1 µmol/L) effectively inhibited the S631A IhERG.
Conclusions:
- The S631A hERG mutation accelerates cardiac repolarization across all studied cardiac regions.
- This mutation is a likely cause of Short QT Syndrome.
- Quinidine demonstrates potential as a therapeutic agent for Short QT Syndrome caused by the S631A mutation.
Abstract:
The hERG potassium channel is critical to normal repolarization of cardiac action potentials (APs) and loss- and gain-of-function hERG mutations are associated, respectively, with long and short QT syndromes, pathological conditions that can lead to arrhythmias and sudden death. hERG current (IhERG ) exhibits uniquely fast inactivation involving conformational changes to the channel pore. The S631A hERG pore mutation was originally engineered to interrogate hERG channel inactivation, but has very recently been found in a family with short QT syndrome (SQTS). Accordingly, this study characterized the effects of the S631A mutation on IhERG profile during ventricular, atrial, and Purkinje fiber (PF) AP waveforms, using patch clamp recording from hERG expressing HEK 293 cells at 37°C. Under conventional voltage clamp, the current-voltage (I-V) relation for IhERG exhibited a marked right-ward shift in the region of negative slope at positive membrane potentials. Under ventricular AP clamp, the S631A mutation resulted in augmented IhERG , which also peaked much earlier during the AP plateau than did wild-type (WT) IhERG . Instantaneous I-V relations showed a marked positive shift in peak repolarizing current during the ventricular AP in the S631A setting, while the instantaneous conductance-voltage relation showed an earlier and more sustained rise in S631A compared to WT IhERG conductance during ventricular repolarization. Experiments with atrial and PF APs in each case also showed augmented and positively shifted IhERG in the S631A setting, indicating that the S631A mutation is likely to accelerate repolarization in all three cardiac regions. Ventricular AP clamp experiments showed retained effectiveness of the class Ia antiarrhythmic drug quinidine (1 micromol/L) against S631A IhERG . Quinidine is thus likely to be effective in reducing excessively fast repolarization in SQTS resulting from the S631A hERG mutation.
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