Potential role of the membrane in hERG channel functioning and drug-induced long QT syndrome.
The human ether-à-go-go related gene (hERG) potassium channels are located in the myocardium cell membrane where they ensure normal cardiac activity. The binding of drugs to this channel, a side effect known as drug-induced (acquired) long QT syndrome (ALQTS), can lead to arrhythmia or sudden cardiac death. The hERG channel is a unique member of the family of voltage-gated K+ channels because of the long extracellular loop connecting its transmembrane S5 helix to the pore helix in the pore domain. Considering the proximal position of the S5-P linker to the membrane surface, we have investigated the interaction of its central segment I(583)-Y(597) with bicelles. Liquid and solid-state NMR experiments as well as circular dichroism results show a strong affinity of the I(583)-Y(597) segment for the membrane where it would sit on the surface with no defined secondary structure. A structural dependence of this segment on model membrane composition was observed. A helical conformation is favoured in detergent micelles and in the presence of negative charges. Our results suggest that the interaction of the S5-P linker with the membrane could participate in the stabilization of transient channel conformations, but helix formation would be triggered by interactions with other hERG domains. Because potential drug binding sites on the S5-P linker have been identified, we have explored the role of this segment in ALQTS. Four LQTS-liable drugs were studied which showed more affinity for the membrane than this hERG segment. Our results, therefore, identify two possible roles for the membrane in channel functioning and ALQTS.
Chartrand
Etienne
E
Department of Chemistry, Pharmaqam/NanoQAM, Université du Québec à Montréal, P.O. Box 8888, Downtown Station, Montreal H3C3P8, Canada.
Arnold
Alexandre A
AA
Gravel
Andrée
A
Jenna
Sarah
S
Marcotte
Isabelle
I
D000595:Amino Acid Sequence; D002462:Cell Membrane / Q000502:physiology*; D002942:Circular Dichroism; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000503:physiopathology; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D011487:Protein Conformation; D015534:Trans-Activators / Q000737:chemistry / Q000502:physiology*; D000071230:Transcriptional Regulator ERG
C072312:ERG protein, human; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG