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.