Abstract
In the malaria vector Anopheles gambiae, two point mutations in the acetylcholinesterase (ace-1R) and the sodium channel (kdrR) 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.
Highlights
In the malaria vector Anopheles gambiae, two point mutations in the acetylcholinesterase and the sodium channel genes confer resistance to organophosphate/carbamate and pyrethroid insecticides, respectively
To the best of our knowledge, in this study we investigate in mosquitoes the neuronal compensatory mechanisms following the development of resistance-associated point mutations in the voltage-gated sodium channels[5,24] and AChE125,26 genes characterized in two strains of Anopheles gambiae resistant to two distinct classes of insecticides, the pyrethroid/DDT-resistant strain, named KdrKis and the organophosphate/ carbamate-resistant strain, named AcerKis
These results suggest the existence of different types of nicotinic acetylcholine receptors (nAChRs) and indicate that the resistance-associated point mutations observed in AcerKis and KdrKis strains differentially affect the cholinergic system involving nAChRs
Summary
In the malaria vector Anopheles gambiae, two point mutations in the acetylcholinesterase (ace-1R) and the sodium channel (kdrR) genes confer resistance to organophosphate/carbamate and pyrethroid insecticides, respectively. A wholegenome microarray approach indicates that overexpression of genes encoding salivary gland proteins can be closely associated with insecticide resistance in Anopheles gambiae[19] Another mechanism recently identified, involves mosquito sensory appendage protein, (e.g., SAP2), a member of chemosensory protein family known to be implicated in the transport of hydrophobic compounds[23]. To the best of our knowledge, in this study we investigate in mosquitoes the neuronal compensatory mechanisms following the development of resistance-associated point mutations in the voltage-gated sodium channels[5,24] and AChE125,26 genes characterized in two strains of Anopheles gambiae resistant to two distinct classes of insecticides, the pyrethroid/DDT-resistant strain, named KdrKis (kdrR, L1014F) and the organophosphate/ carbamate-resistant strain, named AcerKis (ace-1R, G119S). Our results demonstrate that highly complex compensatory mechanisms related to point mutations are essential to be understood for the development of insecticide-based strategies used for mosquito control
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