Buckingham Steven D, Ihara Makoto, Sattelle David B, Matsuda Kazuhiko
Centre for Respiratory Biology, UCL Respiratory, Division of Medicine, University College London, Rayne Building, 5 University Street, London WC1E 6JF. United Kingdom.
Department of Applied Biological Chemistry, Faculty of Agriculture, Kindai University, 3327-204 Nakamachi, Nara 631-8505. Japan.
Curr Med Chem. 2017;24(27):2935-2945. doi: 10.2174/0929867324666170613075736.
γ-Aminobutyric acid (GABA) receptors play a central role in fast inhibitory neurotransmission in insects. Several classes of insecticides targeting insect GABA-gated chloride channels have been developed. The important resistant to dieldrin GABA receptor subunit (RDL) has been used to investigate insecticide sites of action using radioligands, electrophysiology and site-directed mutagenesis. Although this important subunit readily forms robust functional homomeric receptors when expressed, alternative splicing and RNA A-to-I editing can generate diverse forms of the receptor.
We have reviewed studies on native and recombinant insect GABA-gated chloride channels, their interactions with ligands acting at orthosteric and allosteric sites and their interactions with insecticides. Since some GABA receptor modulators act on L-glutamate-gated chloride channels, some comparisons are included.
The actions on GABA-gated chloride channels of polychlorocycloalkanes, cyclodienes, macrocyclic lactones, phenylpyrazoles, isoxazolines, and metadiamides are described and the mechanisms of action of members of these insecticide classes are addressed. Mutations that lead to resistance are discussed as they can be important in developing field diagnostic tests. Toxicity issues relating to insecticides targeting GABA-gated chloride channels are also addressed. An overview of all major insecticide classes targeting insect GABA-gated chloride channels has enhanced our understanding of these important receptors and their insecticide binding sites. However, the subunit composition of native GABA receptors remains unknown and studies to clarify this are needed. Also, the precise sites of action of the recently introduced isoxazolines and meta-diamides will be of interest to pursue.
γ-氨基丁酸（GABA）受体在昆虫快速抑制性神经传递中起核心作用。已开发出几类针对昆虫GABA门控氯离子通道的杀虫剂。重要的抗狄氏剂GABA受体亚基（RDL）已被用于利用放射性配体、电生理学和定点诱变研究杀虫剂的作用位点。尽管该重要亚基在表达时很容易形成强大的功能性同聚体受体，但可变剪接和RNA A到I编辑可产生多种形式的受体。
我们综述了关于天然和重组昆虫GABA门控氯离子通道、它们与作用于正构和变构位点的配体的相互作用以及它们与杀虫剂的相互作用的研究。由于一些GABA受体调节剂作用于L-谷氨酸门控氯离子通道，因此也进行了一些比较。
描述了多氯环烷烃、环二烯、大环内酯、苯基吡唑、异恶唑啉和间二酰胺对GABA门控氯离子通道的作用，并探讨了这些杀虫剂类别的成员的作用机制。讨论了导致抗性的突变，因为它们在开发现场诊断测试中可能很重要。还讨论了与靶向GABA门控氯离子通道的杀虫剂相关的毒性问题。对所有主要靶向昆虫GABA门控氯离子通道的杀虫剂类别的概述增强了我们对这些重要受体及其杀虫剂结合位点的理解。然而，天然GABA受体的亚基组成仍然未知，需要进行研究来阐明这一点。此外，最近引入的异恶唑啉和间二酰胺的确切作用位点也将是值得研究的。
