ArticleProceedings of the National Academy of Sciences of the United States of America2012
Gating pore currents and the resting state of Nav1.4 voltage sensor domains.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers.
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Who cites it
55 citing papers in PubMed.
- Article
- HInternational journal of molecular sciences · 2025Review
- The differential impacts of equivalent gating-charge mutations in voltage-gated sodium channels.The Journal of general physiology · 2025Article
- Understanding the role of mutations in voltage-gated sodium ion channels for cardiovascular disorders.The Journal of general physiology · 2025Article
- Mapping structural distribution and gating-property impacts of disease-associated mutations in voltage-gated sodium channels.iScience · 2024Article
- ELUCIDATING THE DIFFERENTIAL IMPACTS OF EQUIVALENT GATING-CHARGE MUTATIONS IN VOLTAGE-GATED SODIUM CHANNELS.bioRxiv : the preprint server for biology · 2024Article
- Pathogenic gating pore current conducted by autism-related mutations in the NaProceedings of the National Academy of Sciences of the United States of America · 2024Article
- Anionic omega currents from single countercharge mutants in the voltage-sensing domain of Ci-VSP.The Journal of general physiology · 2024Article
- Ion currents through the voltage sensor domain of distinct families of proteins.Journal of biological physics · 2023Review
- Fifty years of gating currents and channel gating.The Journal of general physiology · 2023Review
- Optical measurement of gating pore currents in hypokalemic periodic paralysis model cells.Disease models & mechanisms · 2023Article
- The voltage-sensing domain of a hERG1 mutant is a cation-selective channel.Biophysical journal · 2022Article
- The 70-year search for the voltage-sensing mechanism of ion channels.The Journal of physiology · 2022Article
- 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
- Structural Mechanism of ω-Currents in a Mutated Kv7.2 Voltage Sensor Domain from Molecular Dynamics Simulations.Journal of chemical information and modeling · 2021Article
- Multiscale modeling shows that dielectric differences make NaV channels faster than KV channels.The Journal of general physiology · 2021Article
- New Challenges Resulting From the Loss of Function of NaFrontiers in pharmacology · 2021Review
- pH-Channeling in Cancer: How pH-Dependence of Cation Channels Shapes Cancer Pathophysiology.Cancers · 2020Review
- Roles for Countercharge in the Voltage Sensor Domain of Ion Channels.Frontiers in pharmacology · 2020Review
- Role of the voltage sensor module in NaChannels (Austin, Tex.) · 2019Review
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5 authors.
Funding
Abstract
Mammalian voltage-gated sodium channels are composed of four homologous voltage sensor domains (VSDs; DI, DII, DIII, and DIV) in which their S4 segments contain a variable number of positively charged residues. We used single histidine (H) substitutions of these charged residues in the Na(v)1.4 channel to probe the positions of the S4 segments at hyperpolarized potentials. The substitutions led to the formation of gating pores that were detected as proton leak currents through the VSDs. The leak currents indicated that the mutated residues are accessible from both sides of the membrane. Leak currents of different magnitudes appeared in the DI/R1H, DII/R1H, and DIII/R2H mutants, suggesting that the resting state position of S4 varies depending on the domain. Here, DI/R1H indicates the first arginine R1, in domain DI, has been mutated to histidine. The single R1H, R2H, and R3H mutations in DIV did not produce appreciable proton currents, indicating that the VSDs had different topologies. A structural model of the resting states of the four VSDs of Na(v)1.4 relaxed in their membrane/solution environment using molecular dynamics simulations is proposed based on the recent Na(v)Ab sodium channel X-ray structure. The model shows that the hydrophobic septa that isolate the intracellular and the extracellular media within the DI, DII, and DIII VSDs are ∼2 Å long, similar to those of K(v) channels. However, the septum of DIV is longer, which prevents water molecules from hydrating the center of the VSD, thus breaking the proton conduction pathway. This structural model rationalizes the activation sequence of the different VSDs of the Na(v)1.4 channel.
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