ArticleProceedings of the National Academy of Sciences of the United States of America2009
A recombinant N-terminal domain fully restores deactivation gating in N-truncated and long QT syndrome mutant hERG potassium channels.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 70 papers.
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Who cites it
70 citing papers in PubMed.
- The PAS domain directly regulates hERG channel gating in patch-clamp fluorometry recordings.Biophysical journal · 2026Article
- Chlorpromazine inhibits EAG1 channels by altering the interdomain coupling.Biophysical journal · 2026Article
- Sudden death-associated KCNH2 variants exert opposing effects on a nuclear subdomain of the cardiac potassium channel hERG1.The Journal of biological chemistry · 2026Article
- An ER retention motif controls the heteromeric stoichiometry of hERG1a/1b channels.bioRxiv : the preprint server for biology · 2026Article
- Molecular Determinants of Voltage-Dependent Gating in Kv11.1 Channels.Advances in experimental medicine and biology · 2026Review
- Sudden Death-AssociatedbioRxiv : the preprint server for biology · 2025Article
- Photoinhibition of the hERG potassium channel PAS domain by ultraviolet light speeds channel closing.Biophysical journal · 2024Article
- An intracellular hydrophobic nexus critical for hERG1 channel slow deactivation.Biophysical journal · 2024Article
- A hydrophobic nexus at the heart of hERG K channel gating.Biophysical journal · 2024Article
- Photo-crosslinking hERG channels causes a U.V.-driven, state-dependent disruption of kinetics and voltage dependence of activation.bioRxiv : the preprint server for biology · 2024Article
- Use of Surface Plasmon Resonance Technique for Studies of Inter-domain Interactions in Ion Channels.Methods in molecular biology (Clifton, N.J.) · 2024Article
- An Insight into the Potassium Currents of hERG and Their Simulation.Molecules (Basel, Switzerland) · 2023Article
- hERG1 channel subunit composition mediates proton inhibition of rapid delayed rectifier potassium current (IThe Journal of biological chemistry · 2023Article
- Hysteretic hERG channel gating current recorded at physiological temperature.Scientific reports · 2022Article
- The ERG1 KFrontiers in molecular neuroscience · 2022Review
- Conformation-sensitive antibody reveals an altered cytosolic PAS/CNBh assembly during hERG channel gating.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Electrophysiological characterization of the hERG R56Q LQTS variant and targeted rescue by the activator RPR260243.The Journal of general physiology · 2021Article
- Refinement of a cryo-EM structure of hERG: Bridging structure and function.Biophysical journal · 2021Article
- Gating and regulation of KCNH (ERG, EAG, and ELK) channels by intracellular domains.Channels (Austin, Tex.) · 2020Review
- Structure of KCNH2 cyclic nucleotide-binding homology domain reveals a functionally vital salt-bridge.The Journal of general physiology · 2020Article
10 more citing papers are in PubMed but not listed here.
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2 authors.
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Abstract
Human ether á go-go related gene (hERG) potassium channels play a central role in cardiac repolarization where channel closing (deactivation) regulates current density during action potentials. Consequently, mutations in hERG that perturb deactivation are linked to long QT syndrome (LQTS), a catastrophic cardiac arrhythmia. Interactions between an N-terminal domain and the pore-forming "core" of the channel were proposed to regulate deactivation, however, despite its central importance the mechanistic basis for deactivation is unclear. Here, to more directly examine the mechanism for regulation of deactivation, we genetically fused N-terminal domains to fluorescent proteins and tested channel function with electrophysiology and protein interactions with Förster resonance energy transfer (FRET) spectroscopy. Truncation of hERG N-terminal regions markedly sped deactivation, and here we report that reapplication of gene fragments encoding N-terminal residues 1-135 (the "eag domain") was sufficient to restore regulation of deactivation. We show that fluorophore-tagged eag domains and N-truncated channels were in close proximity at the plasma membrane as determined with FRET. The eag domains with Y43A or R56Q (a LQTS locus) mutations showed less regulation of deactivation and less FRET, whereas eag domains restored regulation of deactivation gating to full-length Y43A or R56Q channels and showed FRET. This study demonstrates that direct, noncovalent interactions between the eag domain and the channel core were sufficient to regulate deactivation gating, that an LQTS mutation perturbed physical interactions between the eag domain and the channel, and that small molecules such as the eag domain represent a novel method for restoring function to channels with disease-causing mutations.
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