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Here, the VGSC of Myzus persicae was characterized using heterologous expression, electrophysiology, structural modeling, and molecular docking. Individual channel fragments failed to produce sodium currents, whereas linker concatenation partially restored activity with reduced amplitude, indicating impaired interdomain coupling. Despite the DENS motif, sodium selectivity was retained, indicating that ion discrimination can be maintained despite alterations in the canonical selectivity filter sequence. Molecular docking predicted genotype-dependent differences in pyrethroid binding modes among variants carrying mutations at positions 918 and 1014, suggesting potential effects on the local binding environment. These findings reveal an evolutionarily distinct functional organization of aphid VGSCs and provide a framework for future investigations into their interactions with pyrethroid insecticides.<\/jats:p>","DOI":"10.1021\/acs.jafc.6c08825","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T08:18:12Z","timestamp":1785140292000},"page":"24234-24243","source":"Crossref","is-referenced-by-count":0,"title":["Structural and Functional Characterization of the\nHeterodimeric Voltage-Gated Sodium Channel in the Green Peach Aphid\n                    <i>Myzus persicae<\/i>"],"prefix":"10.1021","volume":"74","author":[{"given":"Kaiyang","family":"Liu","sequence":"first","affiliation":[{"name":"Hainan University , , ,","place":["Sanya, China, 572024"]},{"name":"Hainan University , , ,","place":["Danzhou, China, 571737"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinglong","family":"Wang","sequence":"additional","affiliation":[{"name":"Hainan University , , ,","place":["Sanya, China, 572024"]},{"name":"Hainan University , , ,","place":["Danzhou, China, 571737"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuran","family":"Xie","sequence":"additional","affiliation":[{"name":"Hainan University , , ,","place":["Sanya, China, 572024"]},{"name":"Hainan University , , ,","place":["Danzhou, China, 571737"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingyao","family":"Qiu","sequence":"additional","affiliation":[{"name":"Hainan University , , ,","place":["Sanya, China, 572024"]},{"name":"Hainan University , , ,","place":["Danzhou, China, 571737"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuxuan","family":"Wen","sequence":"additional","affiliation":[{"name":"Hainan University , , ,","place":["Sanya, China, 572024"]},{"name":"Hainan University , , ,","place":["Danzhou, China, 571737"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4695-5390","authenticated-orcid":true,"given":"Shaoying","family":"Wu","sequence":"additional","affiliation":[{"name":"Hainan University , , ,","place":["Sanya, China, 572024"]},{"name":"Hainan University , , ,","place":["Danzhou, China, 571737"]},{"name":"Hainan University , , Baoting , ,","place":["Haikou, China, 572300"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,7,27]]},"reference":[{"issue":"3","key":"2026081208101496900_cit1","doi-asserted-by":"publisher","first-page":"1994","DOI":"10.1152\/jn.00613.2009","article-title":"Alternative Splicing\nin the Voltage-Gated Sodium Channel DmNav Regulates Activation,\nInactivation, and Persistent Current","volume":"102","author":"Lin","year":"2009","journal-title":"J. Neurophysiol."},{"key":"2026081208101496900_cit2","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.ibmb.2014.03.012","article-title":"Molecular Biology of Insect Sodium\nChannels and Pyrethroid Resistance","volume":"50","author":"Dong","year":"2014","journal-title":"Insect Biochem.\nMol. Biol."},{"issue":"1","key":"2026081208101496900_cit3","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/S0022-3565(24)39034-2","article-title":"Neuroreceptors\nand Ion Channels as the Basis for Drug Action: Past, Present, and\nFuture","volume":"294","author":"Narahashi","year":"2000","journal-title":"J. Pharmacol. Exp. Ther."},{"issue":"1","key":"2026081208101496900_cit4","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1146\/annurev-ento-011118-112420","article-title":"Life and\nDeath at the Voltage-Sensitive Sodium Channel: Evolution in Response\nto Insecticide Use","volume":"64","author":"Scott","year":"2019","journal-title":"Annu. Rev. Entomol."},{"issue":"4","key":"2026081208101496900_cit5","doi-asserted-by":"publisher","first-page":"60","DOI":"10.3390\/insects7040060","article-title":"Sodium Channel Mutations\nand Pyrethroid Resistance in Aedes Aegypti","volume":"7","author":"Du","year":"2016","journal-title":"Insects"},{"issue":"4","key":"2026081208101496900_cit6","doi-asserted-by":"publisher","first-page":"914","DOI":"10.1124\/mol.64.4.914","article-title":"Mutations of the Para Sodium Channel\nof Drosophila Melanogaster Identify Putative Binding Sites for Pyrethroids","volume":"64","author":"Vais","year":"2003","journal-title":"Mol. Pharmacol."},{"key":"2026081208101496900_cit7","doi-asserted-by":"publisher","first-page":"105752","DOI":"10.1016\/j.pestbp.2023.105752","article-title":"Genetics, Genomics and Mechanisms Responsible for High\nLevels of Pyrethroid Resistance in Musca Domestica","volume":"198","author":"Freeman","year":"2024","journal-title":"Pestic. Biochem. Physiol."},{"issue":"3","key":"2026081208101496900_cit8","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1085\/jgp.115.3.305","article-title":"Activation of Drosophila Sodium Channels\nPromotes Modification by Deltamethrin","volume":"115","author":"Vais","year":"2000","journal-title":"J. Gen.\nPhysiol."},{"issue":"1","key":"2026081208101496900_cit9","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s40475-022-00281-6","article-title":"Global\nPattern of Kdr-Type Alleles\nin Musca Domestica (L.)","volume":"10","author":"Roca-Acevedo","year":"2023","journal-title":"Curr. Trop. Med. Rep"},{"key":"2026081208101496900_cit10","doi-asserted-by":"publisher","first-page":"103937","DOI":"10.1016\/j.ibmb.2023.103937","article-title":"The Molecular Mechanisms\nof Insecticide Resistance in Aphid Crop\nPests","volume":"156","author":"Bass","year":"2023","journal-title":"Insect Biochem. Mol. Biol."},{"issue":"5","key":"2026081208101496900_cit11","doi-asserted-by":"publisher","first-page":"598","DOI":"10.1016\/j.febslet.2015.01.020","article-title":"An Evolutionarily-Unique Heterodimeric\nVoltage-Gated\nCation Channel Found in Aphids","volume":"589","author":"Amey","year":"2015","journal-title":"FEBS Lett."},{"issue":"6412","key":"2026081208101496900_cit12","doi-asserted-by":"publisher","DOI":"10.1126\/science.aau2486","article-title":"Structure\nof the Human Voltage-Gated Sodium Channel Nav1.4 in Complex with \u03921","volume":"362","author":"Pan","year":"2018","journal-title":"Science"},{"issue":"7356","key":"2026081208101496900_cit13","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1038\/nature10238","article-title":"The Crystal\nStructure of a Voltage-Gated Sodium Channel","volume":"475","author":"Payandeh","year":"2011","journal-title":"Nature"},{"issue":"16","key":"2026081208101496900_cit14","doi-asserted-by":"publisher","first-page":"6364","DOI":"10.1073\/pnas.1214667110","article-title":"Molecular Dynamics\nof Ion Transport through the Open Conformation of a Bacterial Voltage-Gated\nSodium Channel","volume":"110","author":"Ulmschneider","year":"2013","journal-title":"Proc. Natl. Acad. Sci. U. S.\nA."},{"issue":"8","key":"2026081208101496900_cit15","doi-asserted-by":"publisher","first-page":"820","DOI":"10.15252\/embj.201593285","article-title":"Molecular Basis of Ion Permeability\nin a Voltage-Gated Sodium Channel","volume":"35","author":"Naylor","year":"2016","journal-title":"EMBO J."},{"issue":"28","key":"2026081208101496900_cit16","doi-asserted-by":"publisher","first-page":"11331","DOI":"10.1073\/pnas.1309452110","article-title":"Catalysis\nof Na+ Permeation in the Bacterial Sodium\nChannel Na(V)Ab","volume":"110","author":"Chakrabarti","year":"2013","journal-title":"Proc. Natl. Acad. Sci. U. S.\nA."},{"key":"2026081208101496900_cit17","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1016\/j.cbpb.2016.10.006","article-title":"Characterization\nof an Insect Heterodimeric\nVoltage-Gated Sodium Channel with Unique Alternative Splicing Mode","volume":"203","author":"Jiang","year":"2017","journal-title":"Comp. Biochem. Physiol. B Biochem. Mol. 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Biol."},{"issue":"6","key":"2026081208101496900_cit20","doi-asserted-by":"publisher","first-page":"1001","DOI":"10.1016\/0092-8674(95)90279-1","article-title":"Cloning\nand Functional\nAnalysis of tipE, a Novel Membrane Protein That Enhances Drosophila\nPara Sodium Channel Function","volume":"82","author":"Feng","year":"1995","journal-title":"Cell"},{"issue":"2","key":"2026081208101496900_cit21","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1085\/jgp.110.2.119","article-title":"Functional Expression\nof Drosophila Para Sodium Channels","volume":"110","author":"Warmke","year":"1997","journal-title":"J. Gen. Physiol."},{"issue":"4","key":"2026081208101496900_cit22","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1016\/S0965-1748(01)00122-9","article-title":"Novel Sodium\nChannel Gene Mutations in Blattella Germanica Reduce the Sensitivity\nof Expressed Channels to Deltamethrin","volume":"32","author":"Tan","year":"2002","journal-title":"Insect\nBiochem. Mol. Biol."},{"issue":"7873","key":"2026081208101496900_cit23","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1038\/s41586-021-03819-2","article-title":"Highly Accurate Protein\nStructure Prediction with AlphaFold","volume":"596","author":"Jumper","year":"2021","journal-title":"Nature"},{"issue":"D1","key":"2026081208101496900_cit24","doi-asserted-by":"publisher","first-page":"D1388","DOI":"10.1093\/nar\/gkaa971","article-title":"PubChem in 2021: New Data Content\nand Improved Web Interfaces","volume":"49","author":"Kim","year":"2021","journal-title":"Nucleic Acids Res."},{"issue":"2","key":"2026081208101496900_cit25","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: Improving\nthe Speed and Accuracy of\nDocking with a New Scoring Function, Efficient Optimization, and Multithreading","volume":"31","author":"Trott","year":"2010","journal-title":"J. Comput. Chem."},{"issue":"10","key":"2026081208101496900_cit26","doi-asserted-by":"publisher","first-page":"2778","DOI":"10.1021\/ci200227u","article-title":"LigPlot+: Multiple Ligand\u2013Protein Interaction\nDiagrams for Drug Discovery","volume":"51","author":"Laskowski","year":"2011","journal-title":"J. Chem. Inf. Model."},{"issue":"11","key":"2026081208101496900_cit27","doi-asserted-by":"publisher","first-page":"904","DOI":"10.1038\/s41580-024-00763-7","article-title":"Structural\nBiology and Molecular Pharmacology of Voltage-Gated\nIon Channels","volume":"25","author":"Huang","year":"2024","journal-title":"Nat. Rev. Mol. Cell Biol."},{"issue":"5","key":"2026081208101496900_cit28","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1038\/s41573-024-01108-x","article-title":"Voltage-Gated Sodium\nChannels in Excitable Cells as\nDrug Targets","volume":"24","author":"Alsaloum","year":"2025","journal-title":"Nat. Rev. Drug Discovery"},{"key":"2026081208101496900_cit29","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1146\/annurev.ento.44.1.429","article-title":"The Insect\nVoltage-Gated Sodium Channel as Target of Insecticides","volume":"44","author":"Zlotkin","year":"1999","journal-title":"Annu. Rev. Entomol."},{"key":"2026081208101496900_cit30","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2016.00127","article-title":"Intersubunit Concerted Cooperative\nand Cis-Type Mechanisms\nModulate Allosteric Gating in Two-Pore-Domain Potassium Channel TREK-2","volume":"10","author":"Zhuo","year":"2016","journal-title":"Front. Cell. Neurosci."},{"issue":"3","key":"2026081208101496900_cit31","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1016\/j.vascn.2004.08.014","article-title":"HEK293 Cell Line:\nA Vehicle for the Expression of Recombinant\nProteins","volume":"51","author":"Thomas","year":"2005","journal-title":"J. Pharmacol. Toxicol. Methods"},{"issue":"10","key":"2026081208101496900_cit32","doi-asserted-by":"publisher","first-page":"927","DOI":"10.3390\/membranes12100927","article-title":"The www of Xenopus Laevis Oocytes: The Why, When, What of Xenopus\nLaevis Oocytes in Membrane Transporters Research","volume":"12","author":"Bhatt","year":"2022","journal-title":"Membranes"},{"key":"2026081208101496900_cit33","doi-asserted-by":"publisher","first-page":"106012","DOI":"10.1016\/j.pep.2021.106012","article-title":"Linkers: A Synergistic\nWay for the Synthesis of Chimeric Proteins","volume":"191","author":"Patel","year":"2022","journal-title":"Protein Expr. Purif."},{"issue":"2","key":"2026081208101496900_cit34","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1002\/pro.2206","article-title":"Linkers in\nthe Structural Biology of Protein-Protein Interactions","volume":"22","author":"Reddy Chichili","year":"2013","journal-title":"Protein Sci. Publ. Protein Soc."},{"issue":"1","key":"2026081208101496900_cit35","doi-asserted-by":"publisher","first-page":"1416","DOI":"10.1038\/s41467-022-28984-4","article-title":"Structure-Guided Unlocking\nof NaX Reveals a Non-Selective Tetrodotoxin-Sensitive Cation Channel","volume":"13","author":"Noland","year":"2022","journal-title":"Nat. Commun."},{"issue":"1","key":"2026081208101496900_cit36","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1016\/j.cell.2019.11.041","article-title":"Structure\nof the Cardiac Sodium Channel","volume":"180","author":"Jiang","year":"2020","journal-title":"Cell"},{"issue":"12","key":"2026081208101496900_cit37","doi-asserted-by":"publisher","first-page":"3580","DOI":"10.1021\/ar5002878","article-title":"Ion Selectivity Strategies\nof Sodium Channel Selectivity Filters","volume":"47","author":"Dudev","year":"2014","journal-title":"Acc.\nChem. Res."},{"issue":"10","key":"2026081208101496900_cit38","doi-asserted-by":"publisher","first-page":"829","DOI":"10.1007\/s00359-013-0845-3","article-title":"Naturally Occurring Amino Acid Substitution\nin the Voltage-Dependent Sodium Channel Selectivity Filter Affects\nChannel Gating","volume":"199","author":"Wu","year":"2013","journal-title":"J. Comp. Physiol. A Neuroethol.\nSens. Neural. Behav. Physiol."},{"issue":"11","key":"2026081208101496900_cit39","doi-asserted-by":"publisher","first-page":"4893","DOI":"10.1073\/pnas.89.11.4893","article-title":"Molecular Cloning\nof an Atypical\nVoltage-Gated Sodium Channel Expressed in Human Heart and Uterus:\nEvidence for a Distinct Gene Family","volume":"89","author":"George","year":"1992","journal-title":"Proc. Natl.\nAcad. Sci. U. S. A."},{"issue":"1","key":"2026081208101496900_cit40","doi-asserted-by":"publisher","first-page":"12020","DOI":"10.1038\/s41598-022-16366-1","article-title":"Association\nof Voltage-Gated Sodium Channel Mutations with Field-Evolved Pyrethroid\nResistant Phenotypes in Soybean Aphid and Genetic Markers for Their\nDetection","volume":"12","author":"Valmorbida","year":"2022","journal-title":"Sci. Rep."},{"issue":"29","key":"2026081208101496900_cit41","doi-asserted-by":"publisher","first-page":"11785","DOI":"10.1073\/pnas.1305118110","article-title":"Molecular Evidence\nfor Dual Pyrethroid-Receptor Sites on a Mosquito Sodium Channel","volume":"110","author":"Du","year":"2013","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2026081208101496900_cit42","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1016\/j.neuro.2016.08.013","article-title":"Elucidation of Pyrethroid and DDT\nReceptor Sites in the Voltage-Gated\nSodium Channel","volume":"60","author":"Zhorov","year":"2017","journal-title":"Neurotoxicology"},{"key":"2026081208101496900_cit43","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.ibmb.2017.01.007","article-title":"Mutations\nof Two Acidic Residues at the Cytoplasmic End of Segment IIIS6 of\nan Insect Sodium Channel Have Distinct Effects on Pyrethroid Resistance","volume":"82","author":"Chen","year":"2017","journal-title":"Insect Biochem. Mol. Biol."},{"issue":"8","key":"2026081208101496900_cit44","doi-asserted-by":"publisher","first-page":"745","DOI":"10.3390\/insects13080745","article-title":"Pyrethroids in an AlphaFold2Model\nof the Insect Sodium Channel","volume":"13","author":"Zhorov","year":"2022","journal-title":"Insects"},{"issue":"2","key":"2026081208101496900_cit45","doi-asserted-by":"publisher","first-page":"268","DOI":"10.1016\/j.neulet.2009.12.012","article-title":"Human Embryonic Kidney (HEK293) Cells Express Endogenous\nVoltage-Gated Sodium Currents and Na v 1.7 Sodium Channels","volume":"469","author":"He","year":"2010","journal-title":"Neurosci. Lett."},{"issue":"7","key":"2026081208101496900_cit46","doi-asserted-by":"publisher","first-page":"665","DOI":"10.1007\/s00424-022-02700-z","article-title":"Endogenous\nIon Channels\nExpressed in Human Embryonic Kidney (HEK-293) Cells","volume":"474","author":"Zhang","year":"2022","journal-title":"Pflugers Arch"}],"container-title":["Journal of Agricultural and Food Chemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acs.jafc.6c08825","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/jafcau\/article-pdf\/74\/31\/24234\/66276590\/acs.jafc.6c08825.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/jafcau\/article-pdf\/74\/31\/24234\/66276590\/acs.jafc.6c08825.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T12:38:29Z","timestamp":1786538309000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/jafcau\/article\/74\/31\/24234\/5233734\/Structural-and-Functional-Characterization-of-the"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,27]]},"references-count":46,"journal-issue":{"issue":"31","published-online":{"date-parts":[[2026,7,27]]},"published-print":{"date-parts":[[2026,8,12]]}},"URL":"https:\/\/doi.org\/10.1021\/acs.jafc.6c08825","relation":{},"ISSN":["0021-8561","1520-5118"],"issn-type":[{"value":"0021-8561","type":"print"},{"value":"1520-5118","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,27]]}}}