ArticleProceedings of the National Academy of Sciences of the United States of America2008
Disulfide locking a sodium channel voltage sensor reveals ion pair formation during activation.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 86 papers.
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Who cites it
86 citing papers in PubMed, 127 citations in OpenAlex.
- HInternational journal of molecular sciences · 2025Review
- Voltage sensors.Molecular pharmacology · 2025Review
- The chemistry of electrical signaling in sodium channels from bacteria and beyond.Cell chemical biology · 2024Review
- Dynamics of activation in the voltage-sensing domain of Ciona intestinalis phosphatase Ci-VSP.Nature communications · 2024Article
- Functional effects of drugs and toxins interacting with NaFrontiers in pharmacology · 2024Review
- Voltage gated sodium and calcium channels: Discovery, structure, function, and Pharmacology.Channels (Austin, Tex.) · 2023Review
- Structural surfaceomics reveals an AML-specific conformation of integrin βNature cancer · 2023Article
- Activation and closed-state inactivation mechanisms of the human voltage-gated KMolecular cell · 2022Article
- The 70-year search for the voltage-sensing mechanism of ion channels.The Journal of physiology · 2022Article
- Spliced isoforms of the cardiac Nav1.5 channel modify channel activation by distinct structural mechanisms.The Journal of general physiology · 2022Article
- Sodium channelopathies of skeletal muscle and brain.Physiological reviews · 2021Review
- Charge substitutions at the voltage-sensing module of domain III enhance actions of site-3 and site-4 toxins on an insect sodium channel.Insect biochemistry and molecular biology · 2021Article
- Voltage-dependent structural models of the human Hv1 proton channel from long-timescale molecular dynamics simulations.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Structure and physiological function of the human KCNQ1 channel voltage sensor intermediate state.eLife · 2020Article
- Structure of the Cardiac Sodium Channel.Cell · 2020Article
- Roles for Countercharge in the Voltage Sensor Domain of Ion Channels.Frontiers in pharmacology · 2020Review
- Voltage-dependent gating in K channels: experimental results and quantitative models.Pflugers Archiv : European journal of physiology · 2020Review
- Article
- Illuminating spatial A-to-I RNA editing signatures within theProceedings of the National Academy of Sciences of the United States of America · 2019Article
- Epilepsy-associated mutations in the voltage sensor of KCNQ3 affect voltage dependence of channel opening.The Journal of general physiology · 2019Article
26 more citing papers are in PubMed but not listed here.
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
The S4 transmembrane segments of voltage-gated ion channels move outward on depolarization, initiating a conformational change that opens the pore, but the mechanism of S4 movement is unresolved. One structural model predicts sequential formation of ion pairs between the S4 gating charges and negative charges in neighboring S2 and S3 transmembrane segments during gating. Here, we show that paired cysteine substitutions for the third gating charge (R3) in S4 and D60 in S2 of the bacterial sodium channel NaChBac form a disulfide bond during activation, thus "locking" the S4 segment and inducing slow inactivation of the channel. Disulfide locking closely followed the kinetics and voltage dependence of activation and was reversed by hyperpolarization. Activation of D60C:R3C channels is favored compared with single cysteine mutants, and mutant cycle analysis revealed strong free-energy coupling between these residues, further supporting interaction of R3 and D60 during gating. Our results demonstrate voltage-dependent formation of an ion pair during activation of the voltage sensor in real time and suggest that this interaction catalyzes S4 movement and channel activation.
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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.