Multiple Sites of Insecticidal Action in Ionotropic GABA Receptors

The ionotropic γ-aminobutyric acid (iGABA) receptor is commonly considered as a fast inhibitory channel and is an important insecticide target. Since 1990, RDL, LCCH3, and GRD have been successively isolated and found to be potential subunits of the insect iGABA receptor. More recently, one orphan gene named 8916 was found and considered to be another potential iGABA receptor subunit according to its amino acid sequence. However, little information about 8916 has been reported. Here, the 8916 subunit from Chilo suppressalis was studied to determine whether it can form part of a functional iGABA receptor by co-expressing this subunit with CsRDL1 or CsLCCH3 in the Xenopus oocyte system. Cs8916 or CsLCCH3 did not form functional ion channels when expressed alone. However, Cs8916 was able to form heteromeric ion channels when expressed with either CsLCCH3 or CsRDL1. The recombinant heteromeric Cs8916/LCCH3 channel was a cation-selective channel, which was sensitive to GABA or β-alanine. The current of the Cs8916/LCCH3 channel was inhibited by dieldrin, endosulfan, fipronil, or ethiprole. In contrast, fluralaner, broflanilide, and avermectin showed little effect on the Cs8916/LCCH3 channel (IC50s > 10 000 nM). The Cs8916/RDL1 channel was sensitive to GABA, but was significantly different in EC50 and I max for GABA to those of homomeric CsRDL1. Fluralaner, fipronil, or dieldrin showed antagonistic actions on Cs8916/RDL1. In conclusion, Cs8916 is a potential iGABA receptor subunit, which can interact with CsLCCH3 to generate a cation-selective channel that is sensitive to several insecticides. Also, as Cs8916/RDL1 has a higher EC50 than homomeric CsRDL1, Cs8916 may affect the physiological functions of CsRDL1 and therefore play a role in fine-tuning GABAergic signaling.

Section: ■ Discussionmentioning

confidence: 99%

Functional Characteristics of the Lepidopteran Ionotropic GABA Receptor 8916 Subunit Interacting with the LCCH3 or the RDL Subunit

Huang

Sheng

Jones

et al. 2021

“…GABAR is a well-established target for many insecticides, parasiticides, and acaricides, with various chemical structures. , GABAR antagonists inhibit the activation (opening) of the GABA-gated chloride channel and disturb the normal functioning of GABARs, resulting in insecticidal activity. Conventional anti-GABAergic insecticides found in the 20th century are NCAs of the receptors, including picrotoxinin, lindane, and fipronil (Figure ); these insecticides are divided into first- and second-generation NCAs. , Picrotoxinin isolated from the fruit of Anamirta cocculus is the oldest known naturally occurring NCA and was tested as a prototype insecticide .…”

Section: Conventional Gabar Nca Insecticidesmentioning

confidence: 99%

Potential of Competitive Antagonists of Insect Ionotropic γ-Aminobutyric Acid Receptors as Insecticides

Liu

Gao

et al. 2020

Self Cite

Ionotropic γ-aminobutyric acid (GABA) receptors (GABARs) represent an important insecticide target. Currently used GABAR-targeting insecticides are non-competitive antagonists (NCAs) of these receptors. Recent studies have demonstrated that competitive antagonists (CAs) of GABARs have functions of inhibiting insect GABARs similar to NCAs and that they also exhibit insecticidal activity. CAs have different binding sites and different mechanisms of action compared to those of NCAs. Therefore, GABAR CAs should have the potential to be developed into novel insecticides, which could be used to overcome the developed resistance of insect pests to conventional NCA insecticides. Although research on insect GABAR CAs has lagged behind that on mammalian GABAR CAs, research on the CAs of insect ionotropic GABARs has made great progress in recent years, and several series of heterocyclic compounds, such as 3-isoxazolols and 6-iminopyridazines, have been identified as insect GABAR CAs. In this review, we briefly summarize the design strategies, structures, and biological activities of the novel GABAR CAs that have been found in the past decade. Updated information about GABAR CAs may benefit the design and development of novel GABAR-targeting insecticides.

“…3−5 Ionotropic GABAR (iGABAR) as a transmembrane protein of the Cys-loop ligand-gated ion channel family is essential for neurological function and regulation 6 and thus an important target for many drugs, insecticides, and parasiticides. 7,8 Mammalian iGABAR is termed a type A receptor (GABA A R), with a total of 19 subunits that fall into eight groups (α1−6, β1−3, γ1−3, δ, ε, π, θ, and ρ1−3). 9,10 iGABAR is composed of five subunits, and the major GABA A R subtypes in the brain are formed by the heteromeric combination of double α1, double β2, and single γ subunits.…”

Section: Introductionmentioning

confidence: 99%

5-(4-Pyridinyl)-3-isothiazolols as Competitive Antagonists of Insect GABA Receptors: Design, Synthesis, and a New Mechanism Leading to Insecticidal Effects

Huang

Zhai

et al. 2022

Self Cite

Ionotropic γ-aminobutyric acid (GABA) receptors (iGABARs) are validated targets of drugs and insecticides. Our previous studies showed that the competitive antagonists of insect iGABARs exhibit insecticidal activities and that the 3-isothiazolol scaffold is used as a lead for developing novel iGABAR antagonists. Here, we designed a novel series of 4-aryl-5-(4-pyridinyl)-3isothiazolol (4-API) analogs that have various aromatic substituents at the 4-position. Two-electrode voltage clamp experiments showed that all synthesized 4-APIs exhibited antagonistic activity against Musca domestica and Spodoptera litura iGABARs (RDL) expressed in oocytes of Xenopus laevis at 100 μM. Of the 4-APIs, the 4-(1,1′-biphenylyl) analog was the most potent antagonist with IC 50 s of 7.1 and 9.9 μM against M. domestica and S. litura RDL receptors, respectively. This analog also showed a certain insecticidal activity against S. litura larvae, with >75% mortality at 100 μg/g diet. Molecular docking studies with a M. domestica iGABAR model indicated that the π−π stacking interactions formed between the pyridinyl ring and Y252 and between the 4-substituted aromatic group and Y107 might be important for antagonism by the 4-(1,1′-biphenylyl) analog. Our studies provide important information for designing novel iGABAR antagonists and suggest that the 4-APIs acting on iGABARs are promising insecticide leads for further studies.