GABA receptor subunit composition relative to insecticide potency and selectivity
GABA receptor subunit composition relative to insecticide potency and selectivity
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DOI：
10.1016/s0378-4274(01)00366-6
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发表时间：
2001-07-06
影响因子：
3.5
通讯作者：
Casida, JE
中科院分区：
文献类型：
--
作者：
Ratra, GS;Casida, JE
对γ-氨基丁酸（GABA）受体中的4-[H-3]丙基-4 ' -乙炔基二环原苯甲酸酯（[H-3]EBOB）结合位点的三个观察结果表明了杀虫剂在人脑中作用的特异性靶点和选择性的可能机制。首先，根据已发表的数据，甲型硫丹、林虫腈和氟虫腈在人类重组同源寡聚β 3受体和家蝇头膜中竞争[H-3]EBOB结合位点，亲和力为0.3-7 nM。第二，从结构-活性研究，包括新的数据，GABA能杀虫剂对由β 3亚基形成的五聚体受体的结合效力与对家蝇受体的结合效力良好相关（r = 0.88，n = 20）。这种保守的抑制剂特异性与家蝇GABA受体和人GABA（A）受体β 3亚基中的已知序列同源性一致。第三，作为大多数新的发现，α 1，α 6和γ 2亚基与β 1或β 3亚基共表达的各种组合赋予不同的杀虫剂结合敏感性，特别是对氟虫腈，表明亚基组成是杀虫剂选择性的主要因素。(C)2001爱思唯尔科学爱尔兰有限公司保留所有权利。
Three observations on the 4-[H-3]propyl-4 ' -ethynylbicycloorthobenzoate ([H-3]EBOB) binding site in the gamma -aminobutyric acid (GABA) receptor indicate the specific target for insecticide action in human brain and a possible mechanism for selectivity. First, from published data, alpha -endosulfan, lindane and fipronil compete for the [H-3]EBOB binding site with affinities of 0.3-7 nM in both human recombinant homooligomeric beta3 receptors and housefly head membranes. Second, from structure-activity studies, including new data, GABAergic insecticide binding potency on the pentameric receptor formed from the beta3 subunit correlates well with that on the housefly receptor (r = 0.88, n = 20). This conserved inhibitor specificity is consistent with known sequence homologies in the housefly GABA receptor and the human GABA(A) receptor beta3 subunit. Third, as mostly new findings, various combinations of alpha1, alpha6, and gamma2 subunits coexpressed with a beta1 or beta3 subunit confer differential insecticide binding sensitivity, particularly to fipronil, indicating that subunit composition is a major factor in insecticide selectivity. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.