Mutations in the transmembrane helix S6 of domain IV confer cockroach sodium channel resistance to sodium channel blocker insecticides and local anesthetics.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Jiang, D; Du, Y; Nomura, Y; Wang, X; Wu, Y; Zhorov, BS; Dong, K

Published Date

  • November 2015

Published In

Volume / Issue

  • 66 /

Start / End Page

  • 88 - 95

PubMed ID

  • 26407935

Pubmed Central ID

  • PMC5739882

Electronic International Standard Serial Number (EISSN)

  • 1879-0240

International Standard Serial Number (ISSN)

  • 0965-1748

Digital Object Identifier (DOI)

  • 10.1016/j.ibmb.2015.09.011


  • eng