title: The neonicotinoid imidacloprid, and the pyrethroid deltamethrin, are antagonists of the insect Rdl GABA receptor.
abstract: A mutation in the second transmembrane domain of the GABA receptor subunit, Rdl, is associated with resistance to insecticides such as dieldrin and fipronil. Molecular cloning of Rdl cDNA from a strain of the malaria mosquito, Anopheles gambiae, which is highly resistant to dieldrin revealed this mutation (A296G) as well as another mutation in the third transmembrane domain (T345M). Wild-type, A296G, T345M and A296G + T345M homomultimeric Rdl were expressed in Xenopus laevis oocytes and their sensitivities to fipronil, deltamethrin, 1,1,1-trichloro-2,2-bis(p-chlorophenyl) ethane (DDT), imidacloprid and spinosad were measured using two-electrode voltage-clamp electrophysiology. Spinosad and DDT had no agonist or antagonist actions on Rdl. However, fipronil, deltamethrin and imidacloprid decreased GABA-evoked currents. These antagonistic actions were either reduced or abolished with the A296G and the A296G + T345M mutations while T345M alone appeared to have no significant effect. In conclusion, this study identifies another mutation in the mosquito Rdl that is associated with insecticide resistance. While T345M itself does not affect insecticide sensitivity, it may serve to offset the structural impact of A296G. The present study also highlights Rdl as a potential secondary target for neonicotinoids and pyrethroids. We show for the first time that deltamethrin (a pyrethroid insecticide) and imidacloprid (a neonicotinoid insecticide) act directly on the insect GABA receptor, Rdl. Our findings highlight Rdl as a potential secondary target of pyrethroids and neonicotinoids mutations in which may contribute to resistance to these widely used insecticides.
authors: Faculty of Health and Life Sciences, Department of Biological and Medical Sciences, Oxford Brookes University, Headington, Oxford, UK.
authors: Jennina
authors: J
authors: Taylor-Wells
authors: Wits Research Institute for Malaria, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.|Centre for Opportunistic, Tropical & Hospital Infections, National Institute for Communicable Diseases, NHLS, Johannesburg, South Africa.
authors: Basil D
authors: BD
authors: Brooke
authors: Faculty of Health and Life Sciences, Department of Biological and Medical Sciences, Oxford Brookes University, Headington, Oxford, UK.
authors: Isabel
authors: I
authors: Bermudez
authors: Faculty of Health and Life Sciences, Department of Biological and Medical Sciences, Oxford Brookes University, Headington, Oxford, UK.
authors: Andrew K
authors: AK
authors: Jones
mesh_terms: D000818:Animals; D018118:Chloride Channels / Q000378:metabolism; D009033:Culicidae; D004305:Dose-Response Relationship, Drug; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004347:Drug Interactions; D004558:Electric Stimulation; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D019791:Guanidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D007306:Insecticides / Q000494:pharmacology*; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed / Q000379:methods; D009865:Oocytes; D011722:Pyrethrins / Q000494:pharmacology*; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis / Q000033:anatomy & histology; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: D018118:Chloride Channels; D029721:Drosophila Proteins; D007306:Insecticides; D011722:Pyrethrins; C082030:Rdl protein, Drosophila; D011963:Receptors, GABA-A; C109777:glutamate-gated chloride channels; C506414:neonicotinoid nitroguanidine; D005680:gamma-Aminobutyric Acid; D019791:Guanidine
keywords: Anopheles gambiae; GABA receptor; deltamethrin; fipronil; imidacloprid; insecticide resistance