KCNH2 encodes a nuclear-targeted polypeptide that mediates hERG1 channel gating and expression.

Abstract

KCNH2 encodes hERG1, the voltage-gated potassium channel that conducts the rapid delayed rectifier potassium current (IKr) in human cardiac tissue. hERG1 is one of the first channels expressed during early cardiac development, and its dysfunction is associated with intrauterine fetal death, sudden infant death syndrome, cardiac arrhythmia, and sudden cardiac death. Here, we identified a novel hERG1 polypeptide (hERG1NP) that is targeted to the nuclei of immature cardiac cells, including hiPSC-CMs and neonatal rat cardiomyocytes. The nuclear hERG1NP immunofluorescent signal is diminished in matured hiPSC-CMs and absent from adult rat cardiomyocytes. Antibodies targeting distinct hERG1 channel epitopes demonstrated that the hERG1NP signal maps to the hERG1 distal C-terminal domain. KCNH2 deletion using CRISPR simultaneously abolished IKr and the hERG1NP signal in hiPSC-CMs. We then identified a putative nuclear localization sequence (NLS) within the distal hERG1 C-terminus, 883-RQRKRKLSFR-892. Interestingly, the distal hERG1 C-terminal domain was targeted almost exclusively to the nuclei when overexpressed HEK293 cells. Conversely, deleting the NLS from the distal peptide abolished nuclear targeting. Similarly, blocking α or β1 karyopherin activity diminished nuclear targeting. Finally, overexpressing the distal hERG1 C-terminus significantly reduced hERG1a current density and slowed deactivation, compared to cells expressing GFP. Deleting the NLS from the distal hERG1 C-terminal domain abolished the effects of the distal C-terminus on hERG1a current amplitude and kinetics. These data identify a developmentally regulated polypeptide encoded by KCNH2, hERGNP, whose presence in the nucleus indirectly modulates hERG1 current magnitude and kinetics.