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Effects of intersubunit amino acid substitutions on GABA receptor sensitivity to the ectoparasiticide fluralaner
Pesticide Biochemistry and Physiology ( IF 4.2 ) Pub Date : 2020-02-01 , DOI: 10.1016/j.pestbp.2019.11.001
Kohei Yamato 1 , Yunosuke Nakata 1 , Madoka Takashima 1 , Fumiyo Ozoe 1 , Miho Asahi 2 , Masaki Kobayashi 2 , Yoshihisa Ozoe 1
Affiliation  

The isoxazoline ectoparasiticide fluralaner exerts antiparasitic effects by inhibiting the function of γ-aminobutyric acid (GABA) receptors (GABARs). The present study was conducted to identify the amino acid residues that contribute to the high sensitivity of insect GABARs to fluralaner. We generated housefly (Musca domestica) GABARs with amino acid substitutions in the first through third α-helical transmembrane segments (TM1-TM3) of the RDL subunit using site-directed mutagenesis and examined the effects of the substitutions on the sensitivity of GABARs expressed in Xenopus oocytes to fluralaner using two-electrode voltage clamp electrophysiology. The Q271L substitution in TM1 caused a significant reduction in the sensitivity to fluralaner. Although the I274A and I274F substitutions in TM1 did not affect fluralaner sensitivity, the I274C substitution significantly enhanced the sensitivity to fluralaner. In contrast, the L278C substitution in TM1 reduced fluralaner sensitivity. Substitutions of Gly333 in TM3 led to substantial reductions in the sensitivity to fluralaner. These findings indicate that Gln271, Ile274, Leu278, and Gly333, which are situated in the outer half of the transmembrane subunit interface, are closely related to the antagonism of GABARs by fluralaner.

中文翻译:

亚基间氨基酸取代对 GABA 受体对外寄生物杀虫剂氟乐灵的敏感性的影响

异恶唑啉外驱寄生虫剂氟乐兰能通过抑制 γ-氨基丁酸 (GABA) 受体 (GABAR) 的功能发挥抗寄生虫作用。本研究旨在鉴定有助于昆虫 GABAR 对氟拉纳的高敏感性的氨基酸残基。我们使用定点诱变在 RDL 亚基的第一个到第三个 α-螺旋跨膜片段 (TM1-TM3) 中产生了具有氨基酸取代的家蝇 (家蝇) GABARs,并检查了取代对表达的 GABARs 敏感性的影响使用双电极电压钳电生理学将非洲爪蟾卵母细胞转化为 fluralaner。TM1 中的 Q271L 取代导致对氟拉纳的敏感性显着降低。尽管 TM1 中的 I274A 和 I274F 取代不影响氟拉纳的敏感性,I274C 取代显着增强了对氟拉纳的敏感性。相比之下,TM1 中的 L278C 替代降低了氟拉纳的敏感性。TM3 中 Gly333 的替代导致对氟拉纳的敏感性显着降低。这些发现表明位于跨膜亚基界面外半部分的 Gln271、Ile274、Leu278 和 Gly333 与氟拉纳对 GABARs 的拮抗作用密切相关。
更新日期:2020-02-01
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