Cysteine 723 in the C-linker segment confers oxidative inhibition of hERG1 potassium channels
Copyright policy )Cysteine 723 in the C-linker segment confers oxidative inhibition of hERG1 potassium channels
Excess reactive oxygen species (ROS) play a crucial role under pathophysiological conditions, such as ischaemia/reperfusion and diabetes, potentially contributing to cardiac arrhythmia. hERG1 (KCNH2) potassium channels terminate the cardiac action potential and malfunction can lead to long-QT syndrome and fatal arrhythmia. To investigate the molecular mechanisms of hERG1 channel alteration by ROS, hERG1 and mutants thereof were expressed in HEK293 cells and studied with the whole-cell patch-clamp method. Even mild ROS stress induced by hyperglycaemia markedly decreased channel current. Intracellular H2O2 or cysteine-specific modifiers also strongly inhibited channel activity and accelerated deactivation kinetics. Mutagenesis revealed that cysteine 723 (C723), a conserved residue in a structural element linking the C-terminal domain to the channel's gate, is critical for oxidative functional modification. Moreover, kinetics of channel closure strongly influences ROS-induced modification, where rapid channel deactivation diminishes ROS sensitivity. Because of its fast deactivation kinetics, the N-terminally truncated splice variant hERG1b possesses greater resistance to oxidative modification.
- University of Pennsylvania United States
- Friedrich Schiller University Jena Germany
Models, Molecular, Patch-Clamp Techniques, Protein Conformation, Oxidants, Ether-A-Go-Go Potassium Channels, Recombinant Proteins, Cell Line, Membrane Potentials, Protein Structure, Tertiary, Kinetics, Oxidative Stress, Glucose, Mutation, Mutagenesis, Site-Directed, Potassium Channel Blockers, Humans, Cysteine, Reactive Oxygen Species, Ion Channel Gating, Oxidation-Reduction
Models, Molecular, Patch-Clamp Techniques, Protein Conformation, Oxidants, Ether-A-Go-Go Potassium Channels, Recombinant Proteins, Cell Line, Membrane Potentials, Protein Structure, Tertiary, Kinetics, Oxidative Stress, Glucose, Mutation, Mutagenesis, Site-Directed, Potassium Channel Blockers, Humans, Cysteine, Reactive Oxygen Species, Ion Channel Gating, Oxidation-Reduction
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