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 (I h ERG) 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 I h ERG 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 I h ERG 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 I h ERG, which also peaked much earlier during the AP plateau than did wild‐type (WT) I h ERG. 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 I h ERG conductance during ventricular repolarization. Experiments with atrial and PF APs in each case also showed augmented and positively shifted I h ERG 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 μmol/L) against S631A I h ERG. Quinidine is thus likely to be effective in reducing excessively fast repolarization in SQTS resulting from the S631A hERG mutation.
Highlights
The process of ventricular repolarization in the heart involves the combined activities of a number of potassium (K+) channels (Tamargo et al 2004)
In 2000 a condition called Short QT Syndrome (SQTS), involving abbreviated ventricular repolarization and susceptibility to arrhythmia was first identified (Gussak et al 2000). hERG was the first gene implicated as causing short QT syndrome (SQTS) in 2004, when a missense mutation in the S5-Pore linker region (N588K) of the hERG channel was found in SQTS families (Brugada et al 2004)
These data indicate that peak IhERG block by quinidine was only modestly reduced by the S631A mutation, while the reduction in total charge carried by hERG during the action potentials (APs) command by quinidine was statistically similar between WT and S631A conditions
Summary
The process of ventricular repolarization in the heart involves the combined activities of a number of potassium (K+) channels (Tamargo et al 2004). HERG was the first gene implicated as causing SQTS in 2004, when a missense mutation in the S5-Pore linker region (N588K) of the hERG channel was found in SQTS families (Brugada et al 2004) This mutation leads to a profound positive shift in the voltage dependence of inactivation of IhERG, with the consequence that little inactivation occurs over physiologically relevant membrane potentials and the size and timing of IhERG/IKr during ventricular APs is significantly altered (Cordeiro et al 2005; McPate et al 2005). A subsequent detailed characterization of S631A hERG channels expressed in Xenopus oocytes reported a >100 mV positive shift in half maximal inactivation (Zou et al 1998), while limited AP voltage clamp data from this laboratory, using a modified ventricular AP command, showed a marked effect of the mutation on current timing during the AP (Hancox et al 1998b). The study that is the subject of this report was undertaken: (i) to provide comparative information on the effects of the S631A mutation on the profile of IhERG during atrial, ventricular, and Purkinje fiber APs; (ii) to establish effectiveness of quinidine on S631A IhERG under ventricular AP voltage clamp
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