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

From the Divisions of Molecular Genetics (P.B., G.R.A., B.N., J.K., L.J.D.G.) and Cardiovascular and Metabolic Diseases (C.-M.S., T.R.B., B.J., T.M.A., W.S., T.J.C.), Wyeth-Ayerst Research, Princeton, NJ.

Correspondence to Dr Thomas J. Colatsky, Wyeth-Ayerst Research, PO Box 42528, Philadelphia, PA 19101-2528. E-mail colatst{at}war.wyeth.com

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 (I_kr) 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°C) but not in recordings from intact ventricular strips studied at more physiological rates and temperature (200 to 400 bpm, 37°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 I_Kr in the adult mouse ventricle and demonstrate the ability of the G628S mutation to exert a dominant negative effect on endogenous I_Kr 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.

Key Words: long-QT syndrome • mice, transgenic • HERG • potassium channels • electrocardiography

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