A point mutation in a Drosophila GABA receptor confers insecticide resistance

@article{ffrenchConstant1993APM,
  title={A point mutation in a Drosophila GABA receptor confers insecticide resistance},
  author={R. ffrench-Constant and T. Rocheleau and J. C. Steichen and A. Chalmers},
  journal={Nature},
  year={1993},
  volume={363},
  pages={449-451}
}
VERTEBRATES and invertebrates both have GABA (γ-aminobutyric acid) as a major inhibitory neurotransmitter1,2. GABAA 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 diseases5,6. Picrotoxinin (PTX) and cyclodiene insecticides are GABAA receptor antagonists which competitively displace each other from the same binding site7. Insects8 and vertebrates9… Expand
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Results suggest that target site insensitivity is associated with replacements at the first (A/G) but not the second (S/S′) locus, and may have arisen through a recent gene duplication event with respect to insecticide resistance and insect GABA receptor subunit diversity. Expand
An atypical residue in the pore of Varroa destructor GABA-activated RDL receptors affects picrotoxin block and thymol modulation
TLDR
It is shown that the RDL 6′ residue is important for channel block, activation and modulation, and understanding its function also has the potential to prove useful in the design of Varroa-specific insecticidal agents. Expand
The ligand-gated chloride channel gene family of Drosophila melanogaster
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The present status of knowledge of the structure and function of the proteins encoded by this compact gene family is reviewed, finding that the 12 LCCH genes of D. melanogaster exhibit a surprising degree of structural diversity, which is further enhanced for some subunits by a variety of post-transcriptional and post- translational modifications. Expand
Conservation of cyclodiene insecticide resistance‐associated mutations in insects
TLDR
The finding that precisely the same substitution is present in three pests from three different insect orders is reported, via the use of degenerate primers in the polymerase chain reaction, suggesting that there are a limited number of mutations that can confer resistance to cyclodienes, putative channel blockers, while still maintaining adequate chloride ion channel function. Expand
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TLDR
Identification of new chemistry and multiple potential binding sites for agonists, antagonists, and modulators in these channels suggests potential for developing novel pest control chemicals. Expand
Agonist and antagonist properties of an insect GABA-gated chloride channel (RDL) are influenced by heterologous expression conditions
TLDR
Observations with BtRDL are consistent with previous data obtained with vertebrate glycine receptors and indicates that agonist and antagonist apparent affinity can be influenced by the level of functional expression in a variety of pLGICs. Expand
Molecular biology of the GABA(A) receptor: functional domains implicated by mutational analysis.
TLDR
This review focuses on the application of modern techniques in molecular biology, particularly mutational analysis, to identify structural domains of these receptors that are important for ligand recognition and receptor function. Expand
Pleiotropic Effects of Loss of the Dα1 Subunit in Drosophila melanogaster: Implications for Insecticide Resistance
TLDR
This work used ends-out gene targeting to create a knockout of the Dα1 gene to facilitate phenotypic analysis in a controlled genetic background and reported the first report of a native function for any nAChR subunits known to be targeted by insecticides. Expand
Ion channels as insecticide targets
TLDR
It is found that the insecticide-specific pharmacology of some receptors, like that containing subunits of the Rdl encoded GABA receptor, can be reconstituted with very few of the naturally occurring subunits expressed. Expand
Chloride channels as tools for developing selective insecticides.
  • J. Bloomquist
  • Chemistry, Medicine
  • Archives of insect biochemistry and physiology
  • 2003
TLDR
The mode of action of the silphinenes, plant-derived natural compounds that structurally resemble picrotoxinin, are investigated, which antagonize the action of GABA on insect neurons and block GABA-mediated chloride uptake into mouse brain synaptoneurosomes in a noncompetitive manner. Expand
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It is suggested that the GABAA receptor is the primary target for the action of toxaphene and cyclodiene insecticides but a secondary target for lindane and type II pyrethroids, and the Cl− channel may be aPrimary target for avermectin and lindanes but asecondary one for cyclodienes. Expand
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The atypical M2 segment of the beta subunit confers picrotoxinin resistance to inhibitory glycine receptor channels.
TLDR
Site‐directed mutagenesis identified residues within the second predicted transmembrane segment (M2) of the beta subunit as major determinants of picrotoxinin resistance, which implicate the M2 segment in blocker binding to and lining of the GlyR chloride channel. Expand
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