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Cysteine 723 in the C‐linker segment confers oxidative inhibition of hERG1 potassium channels
Author(s) -
Kolbe Katrin,
Schönherr Roland,
Gessner Guido,
Sahoo Nirakar,
Hoshi Toshinori,
Heinemann Stefan H.
Publication year - 2010
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2010.192468
Subject(s) - chemistry , potassium channel , reactive oxygen species , cysteine , oxidative stress , biophysics , patch clamp , oxidative phosphorylation , intracellular , mutagenesis , biochemistry , microbiology and biotechnology , mutant , receptor , biology , enzyme , gene
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 H 2 O 2 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.