Ratra G S, Casida J E
Environmental Chemistry and Toxicology Laboratory, Department of Environmental Science, Policy and Management, 115 Wellman Hall, University of California, Berkely, CA 94720-3112, USA.
Toxicol Lett. 2001 Jul 6;122(3):215-22. doi: 10.1016/s0378-4274(01)00366-6.
Three observations on the 4-[(3)H]propyl-4'-ethynylbicycloorthobenzoate ([(3)H]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 [(3)H]EBOB binding site with affinities of 0.3--7 nM in both human recombinant homooligomeric beta 3 receptors and housefly head membranes. Second, from structure-activity studies, including new data, GABAergic insecticide binding potency on the pentameric receptor formed from the beta 3 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 beta 3 subunit. Third, as mostly new findings, various combinations of alpha 1, alpha 6, and gamma 2 subunits coexpressed with a beta 1 or beta 3 subunit confer differential insecticide binding sensitivity, particularly to fipronil, indicating that subunit composition is a major factor in insecticide selectivity.
对γ-氨基丁酸（GABA）受体中4-[(³H)]丙基-4'-乙炔基双环原苯甲酸酯（[(³H)]EBOB）结合位点的三项观察结果表明了杀虫剂在人脑中作用的特定靶点以及一种可能的选择性机制。首先，根据已发表的数据，α-硫丹、林丹和氟虫腈在人重组同聚体β3受体和家蝇头部膜中以0.3 - 7 nM的亲和力竞争[(³H)]EBOB结合位点。其次，从包括新数据在内的构效关系研究来看，由β3亚基形成的五聚体受体上的GABA能杀虫剂结合效力与家蝇受体上的效力密切相关（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β3亚基中已知的序列同源性一致。第三，作为主要的新发现，与β1或β3亚基共表达的α1、α6和γ2亚基的各种组合赋予了不同的杀虫剂结合敏感性，特别是对氟虫腈，这表明亚基组成是杀虫剂选择性的一个主要因素。
