AbstractThe hERG potassium channel, which mediates the rapid delayed rectifier current IKr, is critical in determining the duration of cardiac action potentials (APs) and therefore the length of the QT interval. Within the last 15 years, gain-of-function hERG mutations have been identified clinically and these have been shown to abbreviate repolarisation, causing variant 1 of the short QT syndrome (SQT1), with symptoms including atrial fibrillation, syncope and sudden cardiac death. Recently, two new mutations have been associated with SQT1. The first of these, I560T, was published alongside electrophysiological data which showed the mutation to modestly affect hERG inactivation, but a more detailed characterisation of channel properties has not been undertaken. The second mutation, S631A, has been studied in vitro since 1996, when it was shown to cause signification attenuation of inactivation across physiological voltages.
Now that both mutations have been identified clinically, this study aimed to characterise fully the kinetics of I560T-hERG; to investigate the effect of both mutations on hERG current (IhERG) during physiological APs; and to evaluate mutant channels’ affinity for anti-arrhythmic drugs. Using whole-cell patch clamp recordings of wildtype and mutant IhERG in HEK cells, this work shows the I560T mutation to increase IhERG density and attenuate channel inactivation whilst also affecting wider channel properties. These changes lead to augmentation of IhERG during APs and can be expected to increase susceptibility to arrhythmia. Similarly, the attenuation of inactivation caused by the S631A mutation was shown to shift IhERG timing to significantly earlier during repolarisation which can be predicted clinically to abbreviate repolarisation and increase propensity for arrhythmia. Application of quinidine to cells expressing I560T or S631A-hERG showed that the channels’ affinity for the drug was only modestly affected by the mutation, whilst sotalol also retained effectiveness in blocking I560T-hERG, thus suggesting therapeutic options for the identified patients.
|Date of Award||23 Jan 2019|
|Supervisor||Jules C Hancox (Supervisor) & Christopher E Dempsey (Supervisor)|