ArticleThe Journal of biological chemistry2011
Demonstration of physical proximity between the N terminus and the S4-S5 linker of the human ether-a-go-go-related gene (hERG) potassium channel.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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Who cites it
39 citing papers in PubMed.
- Molecular Determinants of Voltage-Dependent Gating in Kv11.1 Channels.Advances in experimental medicine and biology · 2026Review
- An intracellular hydrophobic nexus critical for hERG1 channel slow deactivation.Biophysical journal · 2024Article
- Binding of RPR260243 at the intracellular side of the hERG1 channel pore domain slows closure of the helix bundle crossing gate.Frontiers in molecular biosciences · 2023Article
- Mobility of Lower MA-Helices for Ion Conduction through Lateral Portals in 5-HTBiophysical journal · 2020Article
- hERG Function in Light of Structure.Biophysical journal · 2020Review
- Structures Illuminate Cardiac Ion Channel Functions in Health and in Long QT Syndrome.Frontiers in pharmacology · 2020Review
- The EAG Voltage-Dependent KFrontiers in pharmacology · 2020Review
- Modulation of hERG KFrontiers in pharmacology · 2020Review
- Voltage-dependent activation in EAG channels follows a ligand-receptor rather than a mechanical-lever mechanism.The Journal of biological chemistry · 2019Article
- New Structures and Gating of Voltage-Dependent Potassium (Kv) Channels and Their Relatives: A Multi-Domain and Dynamic Question.International journal of molecular sciences · 2019Review
- Relative positioning of Kv11.1 (hERG) KScientific reports · 2018Article
- Two mutations at different positions in the CNBH domain of the hERG channel accelerate deactivation and impair the interaction with the EAG domain.The Journal of physiology · 2018Article
- Functional characterization of Kv11.1 (hERG) potassium channels split in the voltage-sensing domain.Pflugers Archiv : European journal of physiology · 2018Article
- Gating mechanism of Kv11.1 (hERG) KPflugers Archiv : European journal of physiology · 2018Article
- The S1 helix critically regulates the finely tuned gating of Kv11.1 channels.The Journal of biological chemistry · 2017Article
- Ginsenoside Rg3, a Gating Modifier of EAG Family K+ Channels.Molecular pharmacology · 2016Article
- Enhancement of hERG channel activity by scFv antibody fragments targeted to the PAS domain.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
- Tyrosine Residues from the S4-S5 Linker of Kv11.1 Channels Are Critical for Slow Deactivation.The Journal of biological chemistry · 2016Article
- Structure of the Cyclic Nucleotide-Binding Homology Domain of the hERG Channel and Its Insight into Type 2 Long QT Syndrome.Scientific reports · 2016Article
- Bimodal regulation of an Elk subfamily K+ channel by phosphatidylinositol 4,5-bisphosphate.The Journal of general physiology · 2015Article
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7 authors.
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Abstract
Potassium channels encoded by the human ether-à-go-go-related gene (hERG) contribute to cardiac repolarization as a result of their characteristic gating properties. The hERG channel N terminus acts as a crucial determinant in gating. It is also known that the S4-S5 linker couples the voltage-sensing machinery to the channel gate. Moreover, this linker has been repeatedly proposed as an interaction site for the distal portion of the N terminus controlling channel gating, but direct evidence for such an interaction is still lacking. In this study, we used disulfide bond formation between pairs of engineered cysteines to demonstrate the close proximity between the beginning of the N terminus and the S4-S5 linker. Currents from channels with introduced cysteines were rapidly and strongly attenuated by an oxidizing agent, this effect being maximal for cysteine pairs located around amino acids 3 and 542 of the hERG sequence. The state-dependent modification of the double-mutant channels, but not the single-cysteine mutants, and the ability to readily reverse modification with the reducing agent dithiothreitol indicate that a disulfide bond is formed under oxidizing conditions, locking the channels in a non-conducting state. We conclude that physical interactions between the N-terminal-most segment of the N terminus and the S4-S5 linker constitute an essential component of the hERG gating machinery, thus providing a molecular basis for previous data and indicating an important contribution of these cytoplasmic domains in controlling its unusual gating and hence determining its physiological role in setting the electrical behavior of cardiac and other cell types.
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