ArticleThe Journal of physiology2004
Molecular basis of slow activation of the human ether-a-go-go related gene potassium channel.
Article in The Journal of physiology, 2004. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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Who cites it
41 citing papers in PubMed, 57 citations in OpenAlex.
- Allosteric Mechanisms Underlying Long QT Syndrome Type 2 (LQT2)-Associated Mutations in hERG 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
- An Insight into the Potassium Currents of hERG and Their Simulation.Molecules (Basel, Switzerland) · 2023Article
- Modeling long QT syndrome type 2 on-a-chip via in-depth assessment of isogenic gene-edited 3D cardiac tissues.Science advances · 2022Article
- The voltage-sensing domain of a hERG1 mutant is a cation-selective channel.Biophysical journal · 2022Article
- Cardiac hERG KHandbook of experimental pharmacology · 2021Article
- Selectivity filter modalities and rapid inactivation of the hERG1 channel.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Modulation of hERG KFrontiers in pharmacology · 2020Review
- Importance of the Choice of a Recombinant System to Produce Large Amounts of Functional Membrane Protein hERG.International journal of molecular sciences · 2019Article
- Extracellular protons accelerate hERG channel deactivation by destabilizing voltage sensor relaxation.The Journal of general physiology · 2019Article
- 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 Fast Component of hERG Gating Charge: An Interaction between D411 in the S1 and S4 Residues.Biophysical journal · 2017Article
- Comparative study of the structure and interaction of the pore helices of the hERG and Kv1.5 potassium channels in model membranes.European biophysics journal : EBJ · 2017Article
- Molecular Pathophysiology of Congenital Long QT Syndrome.Physiological reviews · 2017Review
- Mouse ERG K(+) channel clones reveal differences in protein trafficking and function.Journal of the American Heart Association · 2014Article
- Functional interactions of voltage sensor charges with an S2 hydrophobic plug in hERG channels.The Journal of general physiology · 2013Article
- Hydrophobic interactions between the voltage sensor and pore mediate inactivation in Kv11.1 channels.The Journal of general physiology · 2013Article
- Mechanistic basis for type 2 long QT syndrome caused by KCNH2 mutations that disrupt conserved arginine residues in the voltage sensor.The Journal of membrane biology · 2013Article
- Components of gating charge movement and S4 voltage-sensor exposure during activation of hERG channels.The Journal of general physiology · 2013Article
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The human ether-á-go-go related gene (HERG) encodes the pore forming alpha-subunit of the rapid delayed rectifier K(+) channel which is central to the repolarization phase of the cardiac action potential. HERG K(+) channels have unusual kinetics characterized by slow activation and deactivation, yet rapid inactivation. The fourth transmembrane domain (S4) of HERG, like other voltage-gated K(+) channels, contains multiple positive charges and is the voltage sensor for activation. In this study, we mutated each of the positively charged residues in this region to glutamine (Q), expressed the mutant and wild-type (WT) channels in Xenopus laevis oocytes and studied them using two-electrode voltage clamp methods. K525Q channels activated at more hyperpolarized potentials than WT, whereas all the other mutant channels activated at more depolarized potentials. All mutants except for R531Q also had a reduction in apparent gating charge associated with activation. Mutation of K525 to cysteine (C) resulted in a less dramatic phenotype than K525Q. The addition of the positively charged MTSET to K525C altered the phenotype to one more similar to K525Q than to WT. Therefore it is not charge per se, but the specific lysine side chain at position 525, that is crucial for stabilizing the closed state. When rates of activation and deactivation for WT and mutant channels were compared at equivalent total (chemical + electrostatic) driving forces, K525Q and R528Q accelerated activation but had no effect on deactivation, R531Q slowed activation and deactivation, R534Q accelerated activation but slowed deactivation and R537Q accelerated deactivation but had no effect on activation. The main conclusions we can draw from these data are that in WT channels K525 stabilizes the closed state, R531 stabilizes the open state and R534 participates in interactions that stabilize pre-open closed states.
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