Differential Effects of Remdesivir and Lumacaftor on Homomeric and Heteromeric hERG Channels

Abstract

The human ether-a-go-go-related gene (hERG) (KCNH2) encodes the pore-forming a-subunit of the channel (Kv11.1) that conducts the rapidly activating delayed potassium current (IKr) in the heart. The hERG channel is important for the repolarization phase of ventricular action potentials, and mutations causing reduction of its expression in the plasma membrane can result in long QT syndrome type 2 (LQT2). As such, promoting hERG membrane expression is a strategy to rescue mutant channel function. In this study, the rescue effects of two drugs, remdesivir and lumacaftor, on trafficking defective mutant hERG channels were studied by applying patch clamp, Western blot, immunocytochemistry, and Quantitative Reverse Transcription PCR techniques. As our lab has recently reported that the antiviral drug remdesivir, used to treat COVID-19, increases wild-type (WT) hERG current and surface expression, we studied the effects of remdesivir on trafficking defective LQT2-causing hERG mutants G601S and R582 in HEK293 cells. The effects of lumacaftor, a drug used to treat cystic fibrosis that promotes CFTR protein trafficking and has been shown to rescue membrane expression of some hERG mutations, were also investigated. These results show that neither remdesivir nor lumacaftor rescued the current or mature protein expression of homomeric mutant G601S. However, remdesivir decreased while lumacaftor increased the current and mature protein expression of heteromeric channels formed by WT hERG and mutant G601S or R582C. These results demonstrate that drugs can differentially affect homomeric WT and heteromeric mutant-containing hERG channels, extend our understanding of drug-channel interaction, and may have clinical implications for patients with hERG mutations. Remdesivir may exacerbate LQT2, while lumacaftor has potential to mitigate LQT2.