Biophysical analysis of a single amino acid replacement in the resistance to dieldrin gamma-aminobutyric acid receptor: novel dual mechanism for cyclodiene insecticide resistance
1995
Ffrench-Constant, R.H. | Zhang, H.G. | Jackson, M.B.
Target site insensitivity to cyclodienes is associated with a novel insecticide insensitive gamma-aminobutyric acid (GABA) receptor subunit gene termed Resistance to dieldrin (Rdl). To date, examination of this gene in resistant insects from three different orders has always shown the replacement of the same amino acid (alanine302) with either a serine or a glycine (D. simulans only) in the second membrane spanning region (M2) of the receptor. This provides the first direct evidence that cyclodienes and picrotoxinin bind within the M2 region of the receptor, the putative lining of the integral GABA gated chloride ion channel. However, it is unclear why resistance is always only associated with replacements of this single amino acid. We have shown, via a detailed biophysical analysis of the mutated GABA receptor, that the alanine302 > serine replacement has a number of effects on channel function including: reduced sensitivity to picrotoxinin, lindane and TBPS; lower channel conductances; extended open times and shorter closed times and a marked reduction in the rate of GABA-induced receptor desensitization. Via a simple model for evaluating binding site versus allosteric changes, we propose that replacements of alanine302 are the only mutations that can both directly weaken cyclodiene binding to the antagonist favored (desensitized) conformation and indirectly destablilize the antagonist favored conformation through an additional allosteric mechanism. Thus a unique dual resistance mechanism achieves the high levels of target site insensitivity observed.
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