Inhibition of Cardiac Delayed Rectifier K ⁺ Current by Overexpression of the Long-QT Syndrome HERG G628S Mutation in Transgenic Mice

Abstract

Mutations in the HERG gene are linked to the LQT2 form of the inherited long-QT syndrome. Transgenic mice were generated expressing high myocardial levels of a particularly severe form of LQT2-associated HERG mutation (G628S). Hearts from G628S mice appeared normal except for a modest enlargement seen only in females. Ventricular myocytes isolated from adult wild-type hearts consistently exhibited an inwardly rectifying E-4031-sensitive K+ current resembling the rapidly activating cardiac delayed rectifier K+ current (Ikr) in its time and voltage dependence; this current was not found in cells isolated from G628S mice. Action potential duration was significantly prolonged in single myocytes from G628S ventricle (cycle length=1 second, 26 degrees C) but not in recordings from intact ventricular strips studied at more physiological rates and temperature (200 to 400 bpm, 37 degrees C). ECG intervals, including QT duration, were unchanged, although minor aberrancies were noted in 20% (16/80) of the G628S mice studied, primarily involving the QRS complex and, more rarely, T-wave morphology. The aberrations were more commonly observed in females than males but could not be correlated with sex-based differences in action potential duration. These results establish the presence of IKr in the adult mouse ventricle and demonstrate the ability of the G628S mutation to exert a dominant negative effect on endogenous IKr in vivo, leading to the expected LQT2 phenotype of prolonged repolarization at the single cell level but not QT prolongation in the intact animal. The model may be useful in dissecting repolarization currents in the mouse heart and as a means of examining the mechanism(s) by which the G628S mutation exerts its dominant negative effect on native cardiac cells in vivo.

Attenuation of IK,slow1 and IK,slow2 in Kv1/Kv2DN mice prolongs APD and QT intervals but does not suppress spontaneous or inducible arrhythmias

“…We and other investigators have generated genetically modified mice to better understand cardiac repolarization and the pathogenesis of cardiac arrhythmias. Functional attenuation of the rapidly activating component of the K ϩ current (I Kr ) or the slowly activating component of the K ϩ current (I Ks ) in mice did not lead to either QT prolongation or arrhythmogenic substrate (1,9). By contrast, suppression of the expression of Kv1.5-, Kv4.2-or Kv2-encoded currents resulted in prolongation of the QT interval (3,10,14).…”

“…Optical mapping of Kv1DN hearts ex vivo revealed substantially shorter effective refractory periods at the apex of left ventricles compared with the base, causing spatial dispersion of refractoriness and repolarization that formed the base for reentrant arrhythmias (2). Interestingly, none of the other mouse models in which the I Kr (1), I Ks (9), or Kv4.2 (3) channel was functionally knocked out has been reported to have proarrhythmic activity.…”

Zebrafish model for human long QT syndrome

“…To date, an appropriate animal model of inherited LQTS does not exist. Transgenic strategies and targeted deletion of genes that regulate rapidly activating delayed rectifier K ϩ current (I Kr ) and slow delayed rectifier K ϩ current (I Ks ) in mice fail to produce a significant phenotype (5)(6)(7). The mouse heart rate is nearly 10 times faster than that of humans, and thus a distinct cadre of ion channels facilitates ventricular repolarization in mice (5)(6)(7)(8).…”

Properties of WT and mutant hERG K+ channels expressed in neonatal mouse cardiomyocytes

“…A few transgenic animal models have also been created for specific mutations (5,8,23,37). In the present work, we studied the biochemical, biophysical, and pharmacological properties of wild-type (WT) hERG channels and three LQT2-linked channels expressed in native neonatal mouse cardiomyocytes.…”