1. Department of Entomology, 237 Russell Laboratories, 1630 Linden Drive, University of Wisconsin, Madison, Wisconsin 53706, USA
2. ^*Rhône-Poulenc Ag Company, 2 T.W. Alexander Drive, Research Triangle Park, North Carolina 27709, USA

Abstract

VERTEBRATES and invertebrates both have GABA (-aminobutyric acid) as a major inhibitory neurotransmitter^1,2. GABA_A 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 diseases^5,6. Picrotoxinin (PTX) and cyclodiene insecticides are GABA_A 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.