A point mutation in a Drosophila GABA receptor confers insecticide resistance.

Vertebrates and invertebrates both have GABA (gamma-aminobutyric acid) as a major inhibitory neurotransmitter. GABAA receptors in vertebrates assemble as heteromultimers to form an integral chloride ion channel. These receptors are targets for drugs and pesticides and are also implicated in seizure-related diseases. Picrotoxinin (PTX) and cyclodiene insecticides are GABAA receptor antagonists which competitively displace each other from the same binding site. Insects and vertebrates showing resistance to cyclodienes also show cross-resistance to PTX. Previously, we used a field-isolated Drosophila mutant Rdl (Resistant to dieldrin) insensitive to PTX and cyclodienes to clone a putative GABA receptor. 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 populations. This mutation not only identifies a single amino acid conferring high levels of resistance to the important GABA receptor antagonist PTX but also, by conferring resistance to cyclodienes, may account for over 60% of reported cases of insecticide resistance.

The actions of avermectin on crayfish nerve and muscle.

Avermectin is a potent anthelmintic, insecticide and acaricide, which is thought to act by opening GABA (gamma-amino butyric acid)-mediated chloride channels. The effects of avermectin on a crayfish nerve cell (stretch receptor neuron) were compared with those on a muscle (dactyl abductor). Concentrations above 10(-7) M caused a conductance increase and a slight reduction in GABA sensitivity in both nerve and muscle. Lower concentrations potentiated the effect of GABA in muscle, but not in the nerve cell.