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Title: hERG potassium channel electrophysiology and pharmacology in the short QT syndrome
Author: McPate, Mark John William
ISNI:       0000 0001 3389 1063
Awarding Body: University of Bristol
Current Institution: University of Bristol
Date of Award: 2009
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K+ channels mediating the rapid delayed rectifier current (lKr) are encoded by human ether-a-go-go-related gene (hERG) and play an important role in determining cardiac action potential (AP) repolarisation and the QT interval of the electrocardiogram. A gain-of-function hERG mutation (N588K) is associated with variant 1 of the Short QT syndrome (SQT1), which is characterised by short QT intervals «320 ms) and increased risk of cardiac arrhythmias and sudden death. Using whole-cell patch-clamp recordings ofhERG current (lhERG) from Chinese Hamster Ovary cells expressing WildType (WT) or N588K-hERG at 37°C, I investigated the effects of the N588K mutation on hERG channel electrophysiology and pharmacology. The N588K mutation produced a -+60 mV shift in IhERG availability, without concomitant alterations ofthe voltage-dependence of activation or deactivation kinetics OfIhERG. N588K IhERG peaked much earlier than did WT IhERG during guinea-pig and human ventricular AP command waveforms. The N588K mutation also resulted in IhERG peaking earlier during atrial and Purkinje fibre AP commands. MiRP1 co-expression with hERG had little effect on the timing ofpeak repolarising current during AP commands, but did affect maximal IhERG density. Results of experiments using paired AP waveforms raise the possibility that the potentially protective role ofhERG against premature depolarisations may to an extent be compromised for N588K-hERG. The N588K mutation differentially attenuated IhERG block of selected antiarrhythmic drugs. My data indicate that in addition to quinidine, disopyramide and amiodarone may be useful pharmacological treatments for SQT1. Co-expression ofhERG-1a with hERG-1b accelerated WT and N588K IhERG deactivation kinetics and for N588K increased attenuation of inactivation compared to hERG-1a alone. The differences in IhERG-Iallb kinetics as a result of the N588K mutation did not greatly influence currents during AP command waveforms, except that peak repolarising current occurred earlier during the AP than for hERG 1a alone.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available