Expression and Functional Characterization of the Human Ether-à-go-go-Related Gene (HERG) K+ Channel Cardiac Splice Variant in Xenopus laevis Oocytes

Abstract

HERG C(Cardiac), a C-terminal splice variant of the human ether-à-go-go-related gene (HERG A), was identified and found to be 100% homologous to HERG(USO). Real-time polymerase chain reaction data indicated that in the human heart HERG C(Cardiac )mRNA was expressed eight times more than HERG A, whereas in human ventricular tissue it was expressed six times more than HERG A. A HERG C(Cardiac)-green fluorescence protein (GFP) construct was heterologously expressed in Xenopus oocytes. Confocal micrographs revealed that HERG C(Cardiac )was mainly expressed in the plasma membrane. HERG C(Cardiac) channel expressed in oocytes produced slower inactivating outward currents and faster deactivating tail currents than those of HERG A channel. Equal amounts of HERG A and HERG C(Cardiac) cRNA coinjected into oocytes formed intermediate HERG A + HERG C(Cardiac) heteromultimers, which was reconfirmed by immunoprecipitation experiments with a HERG A N-terminal antibody. These heteromultimers had different inactivation, deactivation and activation kinetics from those of HERG A and HERG C(Cardiac) channels. HERG A + HERG C(Cardiac) heteromultimers significantly reduced the model action potential mean amplitude and increased the fast and slow inactivation tau values of the action potential repolarization phase, suggesting involvement of HERG A and HERG C(Cardiac) heteromultimers in modulation of the refractory interval.