ArticleThe Journal of general physiology2003
Negative charges in the transmembrane domains of the HERG K channel are involved in the activation- and deactivation-gating processes.
Article in The Journal of general physiology, 2003. 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, 60 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
- Molecular Determinants of Voltage-Dependent Gating in Kv11.1 Channels.Advances in experimental medicine and biology · 2026Review
- Rare pathogenic mutation ofFrontiers in cardiovascular medicine · 2026Article
- An Insight into the Potassium Currents of hERG and Their Simulation.Molecules (Basel, Switzerland) · 2023Article
- The voltage-sensing domain of a hERG1 mutant is a cation-selective channel.Biophysical journal · 2022Article
- Refinement of a cryo-EM structure of hERG: Bridging structure and function.Biophysical journal · 2021Article
- A novel mutation in KCNH2 yields loss-of-function of hERG potassium channel in long QT syndrome 2.Pflugers Archiv : European journal of physiology · 2021Article
- Modulation of hERG KFrontiers in pharmacology · 2020Review
- The EAG Voltage-Dependent KFrontiers in pharmacology · 2020Review
- Roles for Countercharge in the Voltage Sensor Domain of Ion Channels.Frontiers in pharmacology · 2020Review
- Extracellular protons accelerate hERG channel deactivation by destabilizing voltage sensor relaxation.The Journal of general physiology · 2019Article
- The Fast Component of hERG Gating Charge: An Interaction between D411 in the S1 and S4 Residues.Biophysical journal · 2017Article
- The S1 helix critically regulates the finely tuned gating of Kv11.1 channels.The Journal of biological chemistry · 2017Article
- Coronary Fistulas in a Patient with a Novel Long QT Syndrome Mutation.Arquivos brasileiros de cardiologia · 2015Article
- Voltage sensor gating charge transfer in a hERG potassium channel model.Biophysical journal · 2014Article
- External protons destabilize the activated voltage sensor in hERG channels.European biophysics journal : EBJ · 2014Article
- Functional interactions of voltage sensor charges with an S2 hydrophobic plug in hERG channels.The Journal of general physiology · 2013Article
- Mechanism of loss of Kv11.1 K+ current in mutant T421M-Kv11.1-expressing rat ventricular myocytes: interaction of trafficking and gating.Circulation · 2012Article
- A theoretical model for calculating voltage sensitivity of ion channels and the application on Kv1.2 potassium channel.Biophysical journal · 2012Article
- Voltage-dependent gating of HERG potassium channels.Frontiers in pharmacology · 2012Article
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4 authors at 1 institution in 1 country.
Funding
Abstract
The transmembrane domains of HERG (S1-S3) contain six negative charges: three are conserved in all voltage-gated K channels (D456 and D466 in S2, D501 in S3) and three are unique to the EAG family (D411 in S1, D460 in S2, and D509 in S3). We infer the functional role of these aspartates by studying how substituting them with cysteine, one at a time, affects the channel function. D456C is not functional, suggesting that this negative charge may play a critical role in channel protein folding during biogenesis, as has been shown for its counterpart in the Shaker channel. Data from the other five functional mutants suggest that D411 can stabilize the HERG channel in the closed state, while D460 and D509 have the opposite effect. D466 and D501 both may contribute to voltage-sensing during the activation process. On the other hand, all five aspartates work in a concerted fashion in contributing to the slow deactivation process of the HERG channel. Accessibility tests of the introduced thiol groups to extracellular MTS reagents indicate that water-filled crevices penetrate deep into the HERG protein core, reaching the cytoplasmic halves of S1 and S2. At these deep locations, accessibility of 411C and 466C to the extracellular aqueous phase is voltage dependent, suggesting that conformational changes occur in S1 and S2 or the surrounding crevices during gating. Increasing extracellular [H+] accelerates HERG deactivation. This effect is suppressed by substituting the aspartates with cysteine, suggesting that protonation of these aspartates may contribute to the signaling pathway whereby external [H+] influences conformational changes in the channel's cytoplasmic domains (where deactivation takes place). There is no evidence for a metal ion binding site coordinated by negative charges in the transmembrane domains of HERG, as the one described for the EAG channel.
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