Role of mutation G255A in modulating pyrethroid sensitivity in insect sodium channels

A voltage-gated sodium channel (VGSC) plays a crucial role in insect electrical signals, and it is a target for various naturally occurring and synthesized neurotoxins, including pyrethroids and dichlorodiphenyltrichloroethane. The type of agent is typically widely used to prevent and control sanitary and agricultural pests. The perennial use of insecticides has caused mutations in VGSCs that have given rise to resistance in most insects. These mutations are located among the two pyrethroid receptors, i.e., PyR1 and PyR2, as predicted by previous studies. The two binding regions are relatively symmetrical, and here we focus on the linkers between S4 and S5 of Domains I and II. The S4-S5 linker can promote a rapid increase in sodium current and the onset of action potential. By predicting mutations in 19 other amino acids at all the amino acids on S4-S5 linkers, their harmfulness is analyzed, and whether they affect protein stability and drug binding is determined. Through molecular docking and based on docking scores, four mutations were predicted to affect the binding of sodium channels to pyrethroids. Mutations G255V, G255A, A906V, and A906T were introduced into the VGSC of Blattella germanica (BgNa_v1-1), and their effects on channel gating and pyrethroid sensitivity in Xenopus oocytes were studied. The treatment of VGSCs with two types of pyrethroids (1 nM), Types I (permethrin, bifenthrin) and II (deltamethrin, λ-cyhalothrin), produced tail currents. Among the four, mutant G255A exhibited a certain degree of increased sensitivity to the two types of pyrethroids. This finding was in contrast with the three other mutations, which demonstrated a certain degree of sensitization to one or two pyrethroids. We predicted and validated the critical mutation G255A on the insect VGSC Domain I S4-S5 linker using by electrophysiological technology. In generally, under the pressure of many insecticides, gene modifications, such as transcriptional changes and point mutations in the coding region make insects resistant to insecticides. This phenomenon leads to a higher detoxification rate of insecticides and makes the target site insensitive. However, we found that G255A mutation could promote the combination of pyrethroid and VGSCs by changing the binding force with insecticides. This finding has potential application value in reversing insect resistance. The discovery of mutation G255A exhibits considerable significance for the current use of gene editing and gene drive technology to control pests and delay their resistance development.