A POINT MUTATION IN A DROSOPHILA GABA RECEPTOR CONFERS INSECTICIDE RESISTANCE

VERTEBRATES and invertebrates both have GABA (gamma-aminobutyric acid) as a major inhibitory neurotransmitter1,2. GABA(A) receptors in verte brates assemble as heteromultimers to form an integral chloride ion ch annel3. These receptors are targets for drugs and pesticides4 and are also implicated in seizure-related diseases5,6. Picrotoxinin (PTX) and cyclodiene insecticides are GABA(A) receptor antagonists which compet itively displace each other from the same binding site7. Insects8 and vertebrates9 showing resistance to cyclodienes also show cross-resista nce 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 functiona lity of a resistance-associated point mutation (alanine to serine) wit hin the second membrane-spanning domain, the region thought to line th e chloride ion channel pore. This substitution is found globally in Dr osophila populations12. This mutation not only identifies a single ami no acid conferring high levels of resistance to the important GABA rec eptor antagonist PTX but also, by conferring resistance to cyclodienes , may account for over 60% of reported cases of insecticide resistance 13.