{"doi":"10.1073/pnas.0912307106","title":"Sequential formation of ion pairs during activation of a sodium channel voltage sensor","abstract":"<jats:p>Electrical signaling in biology depends upon a unique electromechanical transduction process mediated by the S4 segments of voltage-gated ion channels. These transmembrane segments are driven outward by the force of the electric field on positively charged amino acid residues termed “gating charges,” which are positioned at three-residue intervals in the S4 transmembrane segment, and this movement is coupled to opening of the pore. Here, we use the disulfide-locking method to demonstrate sequential ion pair formation between the fourth gating charge in the S4 segment (R4) and two acidic residues in the S2 segment during activation. R4 interacts first with E70 at the intracellular end of the S2 segment and then with D60 near the extracellular end. Analysis with the Rosetta Membrane method reveals the 3-D structures of the gating pore as these ion pairs are formed sequentially to catalyze the S4 transmembrane movement required for voltage-dependent activation. Our results directly demonstrate sequential ion pair formation that is an essential feature of the sliding helix model of voltage sensor function but is not compatible with the other widely discussed gating models.</jats:p>","journal":"Proceedings of the National Academy of Sciences","year":2009,"id":45342,"datarank":4.347916543676883,"base_score":4.962844630259907,"endowment":4.962844630259907,"self_citation_contribution":0.7444266945389861,"citation_network_contribution":3.603489849137896,"self_endowment_contribution":0.7444266945389861,"citer_contribution":3.603489849137896,"corpus_percentile":null,"corpus_rank":null,"citation_count":142,"citer_count":107,"citers_with_citation_signal":96,"citers_with_endowment":96,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":117085,"name":"Vladimir Yarov-Yarovoy","orcid":null,"position":1,"is_corresponding":false},{"id":211940,"name":"Elizabeth M. Sharp","orcid":null,"position":2,"is_corresponding":false},{"id":211941,"name":"Todd Scheuer","orcid":null,"position":3,"is_corresponding":false},{"id":211942,"name":"William A. Catterall","orcid":null,"position":4,"is_corresponding":false},{"id":211939,"name":"Paul G. DeCaen","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"base_score":4.962844630259907,"endowment":4.962844630259907,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"20007787","pmcid":"PMC2799717","openalex_id":"https://openalex.org/W2056248932","authors":[],"funders":[{"funder_name":"NINDS NIH HHS","grant_id":"R01 NS015751","title":null},{"funder_name":"NINDS NIH HHS","grant_id":"R01 NS15751","title":null},{"funder_name":"NIGMS NIH HHS","grant_id":"T32 GM07270","title":null},{"funder_name":"NINDS NIH HHS","grant_id":"U01 NS058039","title":null},{"funder_name":"NIGMS NIH HHS","grant_id":"T32 GM007270","title":null}],"total_grants":5,"fwci":4.6559,"citation_percentile":0.95598479,"influential_citations":9,"citation_trend":[{"year":2012,"count":14},{"year":2013,"count":8},{"year":2014,"count":20},{"year":2015,"count":7},{"year":2016,"count":7},{"year":2017,"count":17},{"year":2018,"count":12},{"year":2019,"count":7},{"year":2020,"count":6},{"year":2021,"count":4},{"year":2022,"count":6},{"year":2023,"count":3},{"year":2024,"count":7},{"year":2025,"count":3},{"year":2026,"count":1}],"oa_status":"green","license":null,"oa_locations":[{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/2799717","host_type":"repository"},{"url":"https://europepmc.org/articles/pmc2799717?pdf=render","host_type":"GREEN"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/2799717","host_type":"repository"},{"url":"https://pnas.org/doi/pdf/10.1073/pnas.0912307106","host_type":"publisher"},{"url":"https://doi.org/10.1073/pnas.0912307106","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/20007787","host_type":"repository"}],"fields_of_study":["Ion channel regulation and function","Neuroscience and Neural Engineering","Cardiac electrophysiology and arrhythmias","Chemistry","Medicine","Biology","Physics","Amino Acid Substitution","Bacterial Proteins","Disulfides","Electrophysiological Phenomena","Ion Channel Gating","Kinetics","Models, Biological","Models, Molecular","Mutagenesis, Site-Directed","Patch-Clamp Techniques","Protein Conformation","Recombinant Proteins","Signal Transduction","Sodium Channels"],"mesh_terms":["Bacterial Proteins","Disulfides","Kinetics","Models, Biological","Models, Molecular","Protein Conformation","Recombinant Proteins","Sodium Channels","Signal Transduction","Ion Channel Gating","Mutagenesis, Site-Directed","Patch-Clamp Techniques","Amino Acid Substitution","Electrophysiological Phenomena"],"keywords":["Gating","Transmembrane protein","Ion channel","Biophysics","Transmembrane domain","Voltage-gated ion channel","Chemistry","Ion","Light-gated ion channel","Membrane potential","Sodium channel","Extracellular","Voltage","Helix (gastropod)","Amino acid","Sodium","Biochemistry","Biology","Physics"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Clean water and sanitation"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-07-03T00:46:02.118214Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}