Knock-in mutagenesis in Drosophila Rdl underscores the critical role of the conserved M3 glycine in mediating the actions of broflanilide and isocycloseram on GABA receptors.

γ-Aminobutyric acid receptors (GABARs) are crucial targets for pest control chemicals, including meta-diamide and isoxazoline insecticides, which act as negative allosteric modulators of insect GABARs. Previous cell-based assays have indicated that amino acid residues in the transmembrane cavity between adjacent subunits of Drosophila RDL GABAR (i.e.

Controlled expression of nicotinic acetylcholine receptor-encoding genes in insects uncovers distinct mechanisms of action of the neonicotinoid insecticide dinotefuran.

Dinotefuran, a neonicotinoid, is a unique insecticide owing to its structure and action. We took two approaches that employed insects with controlled expression of nicotinic acetylcholine receptor (nAChR)-encoding genes to gain insight into the uniqueness of dinotefuran. First, we examined the insecticidal activity of dinotefuran and imidacloprid against brown planthoppers (Nilaparvata lugens), in which the expression of eight (of 13) individual subunit-encoding genes was specifically reduced using RNA interference.

Important amino acids for function of the insect Rdl GABA receptor.

Background: Insect Rdl GABA receptor is an important insecticide target. To design a novel insecticide, studies on the structures of homologous pentameric ligand-gated ion channels provide information about important amino acids that are necessary for the function of insect Rdl GABA receptors.

Results: L9'A, T12'A, T13'A, T13'S, M15'S, and M15'N mutations in the Drosophila Rdl GABA receptor subunit caused the protein to spontaneously adopt the open state conformation.

Mechanisms underlying the selectivity of meta-diamides between insect resistance to dieldrin (RDL) and human γ-aminobutyric acid (GABA) and glycine receptors.

Background: Meta-diamides [3-benzamido-N-(4-(perfluoropropan-2-yl)phenyl)benzamides] show high insecticide activity by acting as antagonists to the insect resistance to dieldrin (RDL) γ-aminobutyric acid (GABA) receptors. In contrast, low-level antagonist activities of meta-diamides have been demonstrated against the human GABA type A receptor (GABA R) α1β2γ2S, mammalian GABA R α1β3γ2S, and the human glycine receptor (GlyR) α1β. Glycine residue 336 in the membrane-spanning region M3 of the Drosophila RDL GABA receptor is essential for its high sensitivity to meta-diamide 7, [3-benzamido-N-(2-bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)phenyl)-2-fluorobenzamide].

Insecticides, biologics and nematicides: Updates to IRAC's mode of action classification - a tool for resistance management.

Insecticide resistance has been and continues to be a significant problem for invertebrate pest control. As such, effective insecticide resistance management (IRM) is critical to maintain the efficacy of current and future insecticides. A technical group within CropLife International, the Insecticide Resistance Action Committee (IRAC) was established 35 years ago (1984) as an international association of crop protection companies that today spans the globe.

Differential metabolism of neonicotinoids by brown planthopper, Nilaparvata lugens, CYP6ER1 variants.

Imidacloprid is very effective in controlling Nilaparvata lugens Stål, which severely damages rice plants. Following heavy imidacloprid use, imidacloprid-resistant N. lugens, which showed cross-resistance to other neonicotinoids, appeared.

Differential metabolism of neonicotinoids by CYP6CY3 stably expressed in S2 cells.

The peach-potato aphid, , is a serious crop pest that has developed imidacloprid resistance, mainly through overexpression of CYP6CY3. Here, we established a metabolic assay using S2 cells that stably expressed CYP6CY3. We found that CYP6CY3 showed metabolic activity against imidacloprid, as well as acetamiprid, clothianidin, and thiacloprid, but had no activity against dinotefuran.

Differential metabolism of imidacloprid and dinotefuran by Bemisia tabaci CYP6CM1 variants.

Imidacloprid has been used to control one of most serious pests, Bemisia tabaci. However, B. tabaci has developed imidacloprid resistance mainly by over-expressing CYP6CM1.

Mechanisms of resistance to insecticides targeting RDL GABA receptors in planthoppers.

Lindane and cyclodienes, such as dieldrin and α-endosulfan, represent the first generation of noncompetitive antagonists (NCAs) against the insect RDL GABA receptor. It has been reported that A2'S and A2'G mutations in the membrane-spanning region M2 of the RDL GABA receptor confer resistance to lindane and cyclodienes. Fipronil is a second-generation NCA, but A2'S and A2'G mutations provide a low level of cross-resistance to fipronil.

Broflanilide: A meta-diamide insecticide with a novel mode of action.

Broflanilide is a meta-diamide [3-benzamido-N-(4-(perfluoropropan-2-yl)phenyl)benzamide] that exhibits high larvicidal activity against Spodoptera litura. It has been suggested that broflanilide is metabolized to desmethyl-broflanilide and that it acts as a noncompetitive resistant-to-dieldrin (RDL) γ-aminobutyric acid (GABA) receptor antagonist. The binding site of desmethyl-broflanilide was demonstrated to be distinct from that of conventional noncompetitive antagonists such as fipronil.

Minireview: Mode of action of meta-diamide insecticides.

Meta-diamides [3-benzamido-N-(4-(perfluoropropan-2-yl)phenyl)benzamides] are a distinct class of RDL GABA receptor noncompetitive antagonists showing high insecticidal activity against Spodoptera litura. The mode of action of the meta-diamides was demonstrated to be distinct from that of conventional noncompetitive antagonists (NCAs) such as fipronil, picrotoxin, lindane, dieldrin, and α-endosulfan. It was suggested that meta-diamides act at or near G336 in the M3 region of the Drosophila RDL GABA receptor.

Comparison between the modes of action of novel meta-diamide and macrocyclic lactone insecticides on the RDL GABA receptor.

Macrocyclic lactones, avermectins, and milbemycins are widely used to control arthropods, nematodes, and endo- and ectoparasites in livestock and pets. Their main targets are glutamate-gated chloride channels. Furthermore, macrocyclic lactones reportedly interact with insect RDL γ-aminobutyric acid (GABA) receptors, but their modes of action on insect RDL GABA receptors remain unknown.

Insecticidal 3-benzamido-N-phenylbenzamides specifically bind with high affinity to a novel allosteric site in housefly GABA receptors.

γ-Aminobutyric acid (GABA) receptors (GABARs) are an important target for existing insecticides such as fiproles. These insecticides act as noncompetitive antagonists (channel blockers) for insect GABARs by binding to a site within the intrinsic channel of the GABAR. Recently, a novel class of insecticides, 3-benzamido-N-phenylbenzamides (BPBs), was shown to inhibit GABARs by binding to a site distinct from the site for fiproles.

Meta-diamide insecticides acting on distinct sites of RDL GABA receptor from those for conventional noncompetitive antagonists.

The RDL GABA receptor is an attractive target of insecticides. Here we demonstrate that meta-diamides [3-benzamido-N-(4-(perfluoropropan-2-yl)phenyl)benzamides] are a distinct class of RDL GABA receptor antagonists showing high insecticidal activity against Spodoptera litura. We also suggest that the mode of action of the meta-diamides is distinct from that of conventional noncompetitive antagonists (NCAs), such as fipronil, picrotoxin, lindane, dieldrin, and α-endosulfan.

Concentration-dependent effects of GABA on insensitivity to fipronil in the A2'S mutant RDL GABA receptor from fipronil-resistant Oulema oryzae (Coleoptera: Chrysomelidae).

The beetle Oulema oryzae Kuwayama (Coleoptera: Chrysomelidae), an important pest of rice, has developed fipronil resistance in Japan. Molecular cloning and sequence analysis of O. oryzae RDL gamma-aminobutyric acid (GABA) receptor subunit (OO-RDL) genes from fipronil-susceptible and -resistant O.

The A2'N mutation of the RDL gamma-aminobutyric acid receptor conferring fipronil resistance in Laodelphax striatellus (Hemiptera: Delphacidae).

The planthopper Laodelphax striatellus (Fallén) (Hemiptera: Delphacidae) is a serious insect pest of rice, Oryza sativa L., and has developed resistance to fipronil in Japan. Sequence analysis of L.

Modulation of androgen receptor transcriptional activity by anti-acne reagents.

Background: To study the potential anti-androgenic activity of roxithromycin (RXM), we previously used human dermal fibroblasts transiently transfected with the expression vector of androgen receptor (AR) coactivator ARA55 as the in vitro model reflecting the end-organ hypersensitivity.

Objective: To examine the potential anti-androgenic activity of anti-acne therapeutic agents, nadifloxacin (NDFX), RXM, all-trans retinoic acid (atRA), and glycolic acid (GA), we carried out the transient transfection assays using the CV-1 cells as a more sensitive assay system.

Results: The result showed that 5 microg/ml of RXM suppress 10(-9)M R1881-induced AR transcriptional activity by 21.