A point mutation in a Drosophila GABA receptor confers insecticide resistance

Abstract

VERTEBRATES and invertebrates both have GABA (γ-aminobutyric acid) as a major inhibitory neurotransmitter1,2. GABAA receptors in vertebrates assemble as heteromultimers to form an integral chloride ion channel3. These receptors are targets for drugs and pesticides4 and are also implicated in seizure-related diseases5,6. Picrotoxinin (PTX) and cyclodiene insecticides are GABAA receptor antagonists which competitively displace each other from the same binding site7. Insects8 and vertebrates9 showing resistance to cyclodienes also show cross-resistance to PTX. Previously, we used a field-isolated Drosophila mutant Rdl (Resistant to dieldrin)10 insensitive to PTX and cyclodienes to clone a putative GABA receptor11. Here we report the functional expression and novel pharmacology of this GABA receptor and examine the functionality of a resistance-associated point mutation (alanine to serine) within the second membrane-spanning domain, the region thought to line the chloride ion channel pore. This substitution is found globally in Drosophila populations12. This mutation not only identifies a single amino acid conferring high levels of resist-ance to the important GABA receptor antagonist PTX but also, by conferring resistance to cyclodienes, may account for over 60% of reported cases of insecticide resistance13.

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ffrench-Constant, R., Rocheleau, T., Steichen, J. et al. A point mutation in a Drosophila GABA receptor confers insecticide resistance. Nature 363, 449–451 (1993). https://doi.org/10.1038/363449a0

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