Pestic Biochem Physiol 2025 Sep 02;213:106535. doi: 10.1016/j.pestbp.2025.106535.

Mechanisms of fluralaner antagonism of GABA receptors: A review.

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Ionotropic γ-aminobutyric acid receptors (GABARs) of arthropod pests are the targets of two major groups of insecticides: blockers (IRAC Group 2) and allosteric modulators (IRAC Group 30) of GABA-gated chloride channels. Fluralaner, an isoxazoline ectoparasiticide, acts as an allosteric modulator. Although allosteric modulators antagonized GABARs, the mechanism of their antagonism remained unclear when we undertook the study of fluralaner. This review covers the studies conducted to understand the mechanisms by which fluralaner antagonizes GABARs. To address this challenge, we performed site-directed mutagenesis of housefly (Musca domestica) GABAR RDL subunits and two-electrode voltage-clamp electrophysiological investigations of mutated RDL homomers expressed in Xenopus laevis oocytes. Functional assays revealed that four amino acid residues at the transmembrane subunit interface of the RDL homomer play key roles in fluralaner antagonism. These residues included Q-26' in the M1 segment, N19' in the M2 segment, and G36' and F39' in the M3 segment of the RDL subunit (index numbers are based on the conserved R (0') at the amino terminus of the M2 segment). We also investigated fluralaner antagonism in the activated and resting states of GABARs and found that antagonism progressed in the activated state. Our findings indicate that fluralaner penetrates the intersubunit interface of insect GABARs to interact with key residues, leading to dysfunction of the integral channels.

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