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Ivermectin and fluralaner can disturb the insect nervous system by binding to iGABA receptors, and are therefore an effective means for controlling insect pests. However, the molecular mechanisms underlying the insecticidal effect of both the compounds on <jats:italic>Aedes. aegypti<\/jats:italic> remain unexplored.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>In this study, we investigated the spatiotemporal expression profile of <jats:italic>Ae. aegypti<\/jats:italic> RDL (<jats:italic>Ae\u2010RDL<\/jats:italic>), a subunit of iGABA receptor. <jats:italic>RDL<\/jats:italic> dsRNA suppressed the expression of <jats:italic>Ae\u2010RDL<\/jats:italic> mRNA in <jats:italic>Ae. aegypti<\/jats:italic> larvae and adult by 60% and 50.67%, \u00a0resepectly. However, the physiology of <jats:italic>Ae. aegypti<\/jats:italic> larvae was not significantly affected. The mortality of <jats:italic>Ae. aegypti<\/jats:italic> larvae and adult females subjected to <jats:italic>Ae\u2010RDL<\/jats:italic> knockdown significantly decreased after exposure to ivermectin and fluralaner. Additionally, <jats:italic>Ae\u2010RDL<\/jats:italic> was cloned into <jats:italic>Xenopus laevis<\/jats:italic> oocytes and characterized using the two\u2010electrode voltage\u2010clamp method. The inward current was induced by GABA binding to the functional <jats:italic>Ae\u2010RDL<\/jats:italic> homomeric receptors at a median effective concentration (EC<jats:sub>50<\/jats:sub>) of 100.4\u2009\u00b1\u200959.95\u2009\u03bcM (n\u2009&gt;\u20093). The significant inhibitory effect of ivermectin and fluralaner on inward current indicated that both insecticides exerted a significant antagonistic effect on <jats:italic>Ae\u2010RDL<\/jats:italic>. However, ivermectin also showed strong agonistic as well as weak activation effects on <jats:italic>Ae\u2010RDL<\/jats:italic>. These contrasting effects of ivermectin on <jats:italic>Ae\u2010RDL<\/jats:italic> depended on ivermectin concentration.<\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSION<\/jats:title><jats:p>Our study revealed that <jats:italic>Ae\u2010RDL<\/jats:italic> subunit is a target of ivermectin and fluralaner, providing new insights into the insecticidal mechanism of both compounds in <jats:italic>Ae. aegypti.<\/jats:italic> \u00a9 2022 Society of Chemical Industry.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ps.7035","type":"journal-article","created":{"date-parts":[[2022,6,12]],"date-time":"2022-06-12T06:07:51Z","timestamp":1655014071000},"page":"4173-4182","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Functional analysis reveals ionotropic <scp>GABA<\/scp> receptor subunit <scp>RDL<\/scp> is a target site of ivermectin and fluralaner in the yellow fever mosquito, <i>Aedes 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