ArticlePloS one2012
The S4-S5 linker acts as a signal integrator for HERG K+ channel activation and deactivation gating.
Article in PloS one, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 45 citations in OpenAlex.
- Integrating AI and Molecular Modeling for Structural Prediction of a Closed-Pore State of the hERG Channel.Journal of chemical information and modeling · 2026Article
- The Role of Loss-of-Function KCNH2 Variants in Cardiac Arrhythmias, Seizures and the Risk of Sudden Unexpected Death in Epilepsy.Journal of neurochemistry · 2026Review
- Molecular Determinants of Voltage-Dependent Gating in Kv11.1 Channels.Advances in experimental medicine and biology · 2026Review
- hERG1 channel subunit composition mediates proton inhibition of rapid delayed rectifier potassium current (IThe Journal of biological chemistry · 2023Article
- Precise in vivo functional analysis of DNA variants with base editing using ACEofBASEs target prediction.eLife · 2022Article
- Electrophysiological characterization of the hERG R56Q LQTS variant and targeted rescue by the activator RPR260243.The Journal of general physiology · 2021Article
- Electrophysiological characterization of the modified hERGPhysiological reports · 2020Article
- The EAG Voltage-Dependent KFrontiers in pharmacology · 2020Review
- Modulation of hERG KFrontiers in pharmacology · 2020Review
- Extracellular protons accelerate hERG channel deactivation by destabilizing voltage sensor relaxation.The Journal of general physiology · 2019Article
- 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
- hERG S4-S5 linker acts as a voltage-dependent ligand that binds to the activation gate and locks it in a closed state.Scientific reports · 2017Article
- Tyrosine Residues from the S4-S5 Linker of Kv11.1 Channels Are Critical for Slow Deactivation.The Journal of biological chemistry · 2016Article
- Rescue of protein expression defects may not be enough to abolish the pro-arrhythmic phenotype of long QT type 2 mutations.The Journal of physiology · 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
- Conservation analysis of residues in the S4-S5 linker and the terminal part of the S5-P-S6 pore modulus in Kv and HCN channels: flexible determinants for the electromechanical coupling.Pflugers Archiv : European journal of physiology · 2015Article
- An Interdomain KCNH2 Mutation Produces an Intermediate Long QT Syndrome.Human mutation · 2015Article
- Getting to the heart of hERG K(+) channel gating.The Journal of physiology · 2015Review
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Human ether-à-go-go-related gene (hERG) K(+) channels have unusual gating kinetics. Characterised by slow activation/deactivation but rapid inactivation/recovery from inactivation, the unique gating kinetics underlie the central role hERG channels play in cardiac repolarisation. The slow activation and deactivation kinetics are regulated in part by the S4-S5 linker, which couples movement of the voltage sensor domain to opening of the activation gate at the distal end of the inner helix of the pore domain. It has also been suggested that cytosolic domains may interact with the S4-S5 linker to regulate activation and deactivation kinetics. Here, we show that the solution structure of a peptide corresponding to the S4-S5 linker of hERG contains an amphipathic helix. The effects of mutations at the majority of residues in the S4-S5 linker of hERG were consistent with the previously identified role in coupling voltage sensor movement to the activation gate. However, mutations to Ser543, Tyr545, Gly546 and Ala548 had more complex phenotypes indicating that these residues are involved in additional interactions. We propose a model in which the S4-S5 linker, in addition to coupling VSD movement to the activation gate, also contributes to interactions that stabilise the closed state and a separate set of interactions that stabilise the open state. The S4-S5 linker therefore acts as a signal integrator and plays a crucial role in the slow deactivation kinetics of the channel.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.