γ-Aminobutyric Acid Receptors: A Rationale for Developing Selective Insect Pest Control Chemicals

Ozoe, Yoshihisa; Takeda, Makio; Matsuda, Kazuhiko

doi:10.1007/978-90-481-2316-2_6

Cited by 15 publications

(18 citation statements)

References 173 publications

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“…It was soon recognized that broad cross-resistance to polychlorocycloalkanes was conferred by this A2'S mutation [40] but to varying degrees for dieldrin, α-endosulfan, fipronil and other NCA-IA compounds. Site-directed mutagenesis, cysteine scanning and molecular modeling of the NCA-IA target established the importance of interactions with channel-lining residues A2', T6' and L9' [6,7,16,41], a conclusion which is essentially unchanged when updated based on the docking positions for fipronil and EBOB (Fig. 2) in our current models.…”

Section: Nca Action Resistance and Binding Sitesmentioning

confidence: 88%

“…GABA is the principal inhibitory neurotransmitter in the insect and mammalian nervous systems [5][6][7][8][9][10][11]. Ionotropic GABA-Rs are ligand-gated chloride channels consisting of five heteromeric subunits in mammals (usually two α subunits.…”

Section: Structure and Functionmentioning

confidence: 99%

“…The receptor preparations considered here are generally mammalian brain membranes and expressed GABAAR β3 homopentamer compared with Musca and Dm head membranes and expressed RDL GABA-R. NCA-IA compounds are only moderately selective between insects and mammals and their GABA-Rs although lindane is somewhat more selective than the cyclodienes [13]. The selectivity is improved with fiproles [77] optimized from a great variety of insecticidal heterocycles [4,7]. NCA-IB compounds are highly toxic cage convulsants to mammals leading to their use as rodenticides and importance as chemical threat agents.…”

Section: Selective Toxicitymentioning

confidence: 99%

“…Any novel target is therefore a valuable contribution not only to science but also to human welfare. The γ-aminobutyric acid (GABA) receptor (GABA-R) is the target for many insecticides, acaricides, anthelmintics and rodenticides of widely varied structures [2][3][4][5][6][7][8]. The extracellular and transmembrane domains also have multiple targets for other antagonists, agonists and modulators of various types.…”

Section: Gabaergic Pesticidesmentioning

confidence: 99%

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Novel GABA receptor pesticide targets

Casida

Durkin

2015

Pesticide Biochemistry and Physiology

114

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The γ-aminobutyric acid (GABA) receptor has four distinct but overlapping and coupled targets of pesticide action importantly associated with little or no cross-resistance. The target sites are differentiated by binding assays with specific radioligands, resistant strains, site-directed mutagenesis and molecular modeling. Three of the targets are for non-competitive antagonists (NCAs) or channel blockers of widely varied chemotypes. The target of the first generation (20th century) NCAs differs between the larger or elongated compounds (NCA-IA) including many important insecticides of the past (cyclodienes and polychlorocycloalkanes) or present (fiproles) and the smaller or compact compounds (NCA-IB) highly toxic to mammals and known as cage convulsants, rodenticides or chemical threat agents. The target of greatest current interest is designated NCA-II for the second generation (21st century) of NCAs consisting for now of isoxazolines and meta-diamides. This new and uniquely different NCA-II site apparently differs enough between insects and mammals to confer selective toxicity. The fourth target is the avermectin site (AVE) for allosteric modulators of the chloride channel. NCA pesticides vary in molecular surface area and solvent accessible volume relative to avermectin with NCA-IBs at 20-22%, NCA-IAs at 40-45% and NCA-IIs at 57-60%. The same type of relationship relative to ligand-docked length is 27-43% for NCA-IBs, 63-71% for NCA-IAs and 85-105% for NCA-IIs. The four targets are compared by molecular modeling for the Drosophila melanogaster GABA-R. The principal sites of interaction are proposed to be: pore V1' and A2' for NCA-IB compounds; pore A2', L6' and T9' for NCA-IA compounds; pore T9' to S15' in proximity to M1/M3 subunit interface (or alternatively an interstitial site) for NCA-II compounds; and M1/M3, M2 interfaces for AVE. Understanding the relationships of these four binding sites is important in resistance management and in the discovery and use of safe and effective pest control agents.

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Section: Nca Action Resistance and Binding Sitesmentioning

confidence: 88%

Section: Structure and Functionmentioning

confidence: 99%

Section: Selective Toxicitymentioning

confidence: 99%

Section: Gabaergic Pesticidesmentioning

confidence: 99%

See 2 more Smart Citations

Novel GABA receptor pesticide targets

Casida

Durkin

2015

Pesticide Biochemistry and Physiology

114

View full text Add to dashboard Cite

show abstract

“…1). 3 2,6,7‐Trioxa‐1‐phosphabicyclo[2.2.2]octane‐1‐sulfides (bicyclophosphorothionates) and 1‐oxides are blockers (or non‐competitive antagonists) of ionotropic GABA receptors. These molecules show acute toxicity for vertebrates and insecticidal activity for insects 4–8.…”

Section: Introductionmentioning

confidence: 99%