Silver Kristopher S, Soderlund David M
Department of Entomology, New York State Agricultural Experiment Station, Cornell University, PO Box 462, Geneva, NY 14456, USA.
Toxicol Appl Pharmacol. 2006 Jul 15;214(2):209-17. doi: 10.1016/j.taap.2005.12.018. Epub 2006 Feb 17.
Pyrazoline-type insecticides are potent inhibitors of insect and mammalian voltage-sensitive sodium channels. In mammals, there are nine sodium channel alpha subunit isoforms that have unique distributions and pharmacological properties, but no published data exist that compare the relative sensitivity of these different mammalian sodium channel isoforms to inhibition by pyrazoline-type insecticides. This study employed the Xenopus oocyte expression system to examine the relative sensitivity of rat Na(v)1.2a, Na(v)1.4, Na(v)1.5, and Na(v)1.8 sodium channel alpha subunit isoforms to the pyrazoline-type insecticides indoxacarb, DCJW, and RH 3421. Additionally, we assessed the effect of coexpression with the rat beta1 auxiliary subunit on the sensitivity of the Na(v)1.2a and Na(v)1.4 isoforms to these compounds. The relative sensitivity of the four sodium channel alpha subunits differed for each of the three compounds we examined. With DCJW, the order of sensitivity was Na(v)1.4 > Na(v)1.2a > Na(v)1.5 > Na(v)1.8. In contrast, the relative sensitivity of these isoforms to indoxacarb differed from that to DCJW: the Na(v)1.8 isoform was most sensitive, the Na(v)1.4 isoform was completely insensitive, and the sensitivities of the Na(v)1.5 and Na(v)1.2a isoforms were intermediate between these two extremes. Moreover, the pattern of sensitivity to RH 3421 among these four isoforms was different from that for either indoxacarb or DCJW: the Na(v)1.4 isoform was most sensitive to RH 3421, whereas the sensitivities of the remaining three isoforms were substantially less than that of the Na(v)1.4 isoform and were approximately equivalent. The only statistically significant effect of coexpression of either the Na(v)1.2a or Na(v)1.4 isoforms with the beta1 subunit was the modest reduction in the sensitivity of the Na(v)1.2a isoform to RH 3421. These results demonstrate that mammalian sodium channel isoforms differ in their sensitivities to pyrazoline-type insecticides.
吡唑啉类杀虫剂是昆虫和哺乳动物电压门控性钠通道的强效抑制剂。在哺乳动物中，有九种钠通道α亚基同工型，它们具有独特的分布和药理特性，但尚无已发表的数据比较这些不同的哺乳动物钠通道同工型对吡唑啉类杀虫剂抑制作用的相对敏感性。本研究采用非洲爪蟾卵母细胞表达系统，检测大鼠Na(v)1.2a、Na(v)1.4、Na(v)1.5和Na(v)1.8钠通道α亚基同工型对吡唑啉类杀虫剂茚虫威、DCJW和RH 3421的相对敏感性。此外，我们评估了与大鼠β1辅助亚基共表达对Na(v)1.2a和Na(v)1.4同工型对这些化合物敏感性的影响。我们检测的三种化合物中，四种钠通道α亚基的相对敏感性各不相同。对于DCJW，敏感性顺序为Na(v)1.4 > Na(v)1.2a > Na(v)1.5 > Na(v)1.8。相比之下，这些同工型对茚虫威的相对敏感性与对DCJW的不同：Na(v)1.8同工型最敏感，Na(v)1.4同工型完全不敏感，Na(v)1.5和Na(v)1.2a同工型的敏感性介于这两个极端之间。此外，这四种同工型对RH 3421的敏感性模式与对茚虫威或DCJW的不同：Na(v)1.4同工型对RH 3421最敏感，而其余三种同工型的敏感性远低于Na(v)1.4同工型且大致相当。Na(v)1.2a或Na(v)1.4同工型与β1亚基共表达的唯一统计学显著效应是Na(v)1.2a同工型对RH 3421的敏感性适度降低。这些结果表明，哺乳动物钠通道同工型对吡唑啉类杀虫剂的敏感性不同。
