title: Mutations in the transmembrane helix S6 of domain IV confer cockroach sodium channel resistance to sodium channel blocker insecticides and local anesthetics.
abstract: Indoxacarb and metaflumizone are two sodium channel blocker insecticides (SCBIs). They preferably bind to and trap sodium channels in the slow-inactivated non-conducting state, a mode of action similar to that of local anesthetics (LAs). Recently, two sodium channel mutations, F1845Y (F(4i15)Y) and V1848I (V(4i18)I), in the transmembrane segment 6 of domain IV (IVS6), were identified to be associated with indoxacarb resistance in Plutella xylostella. F(4i15) is known to be critical for the action of LAs on mammalian sodium channels. Previously, mutation F(4i15)A in a cockroach sodium channel, BgNav1-1a, has been shown to reduce the action of lidocaine, a LA, but not the action of SCBIs. In this study, we introduced mutations F(4i15)Y and V(4i18)A/I individually into the cockroach sodium channel, BgNav1-1a, and conducted functional analysis of the three mutants in Xenopus oocytes. We found that both the F(4i15)Y and V(4i18)I mutations reduced the inhibition of sodium current by indoxacarb, DCJW (an active metabolite of indoxacarb) and metaflumizone. F(4i15)Y and V(4i18)I mutations also reduced the use-dependent block of sodium current by lidocaine. In contrast, substitution V(4i18)A enhanced the action metaflumizone and lidocaine. These results show that both F(4i15)Y and V(4i18)I mutations may contribute to target-site resistance to SCBIs, and provide the first molecular evidence for common amino acid determinants on insect sodium channels involved in action of SCBIs and LA.
authors.affiliation: Key Laboratory of Natural Pesticide and Chemical Biology, Ministry of Education, Laboratory of Insect Toxicology, South China Agricultural University, Guangzhou, China; Department of Entomology, Neuroscience and Genetics Programs, Michigan State University, East Lansing, MI, USA.
authors.forename: Dingxin
authors.initials: D
authors.lastname: Jiang
authors.affiliation: Department of Entomology, Neuroscience and Genetics Programs, Michigan State University, East Lansing, MI, USA.
authors.forename: Yuzhe
authors.initials: Y
authors.lastname: Du
authors.affiliation: Department of Entomology, Neuroscience and Genetics Programs, Michigan State University, East Lansing, MI, USA.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Nomura
authors.affiliation: College of Plant Protection, Nanjing Agricultural University, Nanjing, China.
authors.forename: Xingliang
authors.initials: X
authors.lastname: Wang
authors.affiliation: College of Plant Protection, Nanjing Agricultural University, Nanjing, China.
authors.forename: Yidong
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada; Sechenov Institute of Evolutionary Physiology & Biochemistry, Russian Academy of Sciences, St. Petersburg, Russia.
authors.forename: Boris S
authors.initials: BS
authors.lastname: Zhorov
authors.affiliation: Department of Entomology, Neuroscience and Genetics Programs, Michigan State University, East Lansing, MI, USA. Electronic address: dongk@msu.edu.
authors.forename: Ke
authors.initials: K
authors.lastname: Dong
mesh_terms: D000779:Anesthetics, Local / Q000494:pharmacology*; D000818:Animals; D003058:Cockroaches / Q000187:drug effects* / Q000235:genetics; D019476:Insect Proteins / Q000235:genetics / Q000378:metabolism*; D007305:Insecticide Resistance / Q000235:genetics; D007306:Insecticides / Q000494:pharmacology*; D008012:Lidocaine / Q000494:pharmacology; D009154:Mutation; D009865:Oocytes / Q000378:metabolism; D010078:Oxazines / Q000494:pharmacology; D000072417:Protein Domains; D012664:Semicarbazones / Q000494:pharmacology; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*; D014981:Xenopus
chemical_list: D000779:Anesthetics, Local; D019476:Insect Proteins; D007306:Insecticides; D010078:Oxazines; D012664:Semicarbazones; D026941:Sodium Channel Blockers; D015222:Sodium Channels; C401104:indoxacarb; C528570:metaflumizone; D008012:Lidocaine
keywords: Insecticide resistance; Local anesthetics; Sodium channel; Sodium channel blocker insecticides