Compensatory mechanisms in resistant Anopheles gambiae AcerKis and KdrKis neurons modulate insecticide-based mosquito control

In the malaria vector Anopheles gambiae, two point mutations in the acetylcholinesterase (ace-1(R)) and the sodium channel (kdr(R)) genes confer resistance to organophosphate/carbamate and pyrethroid insecticides, respectively. The mechanisms of compensation that recover the functional alterations associated with these mutations and their role in the modulation of insecticide efficacy are unknown. Using multidisciplinary approaches adapted to neurons isolated from resistant Anopheles gambiae AcerKis and KdrKis strains together with larval bioassays, we demonstrate that nAChRs, and the intracellular calcium concentration represent the key components of an adaptation strategy ensuring neuronal functions maintenance. In AcerKis neurons, the increased effect of acetylcholine related to the reduced acetylcholinesterase activity is compensated by expressing higher density of nAChRs permeable to calcium. In KdrKis neurons, changes in the biophysical properties of the L1014F mutant sodium channel, leading to enhance overlap between activation and inactivation relationships, diminish the resting membrane potential and reduce the fraction of calcium channels available involved in acetylcholine release. Together with the lower intracellular basal calcium concentration observed, these factors increase nAChRs sensitivity to maintain the effect of low concentration of acetylcholine. These results explain the opposite effects of the insecticide clothianidin observed in AcerKis and KdrKis neurons in vitro and in vivo. Perrier et al. examine the neurons of mosquitoes following the development of insecticide resistance-associated point mutations in the voltage-gated sodium channels and AChE1 genes for two resistant strains, KdrKis and AcerKis. Their results show that nAChRs and the intracellular calcium concentration provide a compensatory mechanism for AcerKis and KdrKis neurons to insecticide exposure.

Automated summary

Researchers found that nAChRs and intracellular calcium concentration provide a compensatory mechanism for the neurons of two resistant mosquito strains, AcerKis and KdrKis, to insecticide exposure.