Pharmacological and Genetic Evidence for Gap Junctions as Potential New Insecticide Targets in the Yellow Fever Mosquito, Aedes aegypti.
Pharmacological and Genetic Evidence for Gap Junctions as Potential New Insecticide Targets in the Yellow Fever Mosquito, Aedes aegypti.
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间隙连接的药理学和遗传证据是黄热病蚊子埃德斯埃及的潜在新杀虫剂靶标。
DOI：
10.1371/journal.pone.0137084
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Piermarini PM
中科院分区：
文献类型：
--
作者：
Calkins TL;Piermarini PM
黄热病蚊子埃及伊蚊是影响全球健康的病毒性疾病的重要媒介。杀虫剂通常用于控制蚊子种群，但杀虫剂抗药性的演变限制了其有效性。因此，需要确定蚊子中新的分子和生理目标，以促进杀虫剂的发现和开发。在这里，我们测试了间隙连接是新型杀虫剂的有效分子和生理目标的假设。间隙连接是介导相邻细胞之间直接通讯的细胞间通道，由脊椎动物（连接蛋白）和无脊椎动物（内连接蛋白）中进化上不同的蛋白质组成。我们发现，将间隙连接的药理学抑制剂（即甲苯索隆、甲氯芬那酸或甲氟喹）注射到成年雌性蚊子的血淋巴中会引起剂量依赖性毒性作用，其中甲氟喹显示出最大的效力。相比之下，当局部应用于角质层时，生甲酚是唯一表现出完全功效的抑制剂。体内尿液排泄测定表明，生甲酚和甲氟喹都会抑制成年雌性蚊子的利尿输出，表明排泄功能的抑制是其作用机制的一部分。当添加到一龄幼虫的饲养水中时，生甲酚和甲氯芬那酸都会引起剂量依赖性毒性作用，其中甲氯芬那酸显示出最大的效力。将针对 innexins 的双链 RNA 混合物注射到成年雌性蚊子的血淋巴中，会降低整个动物的 innexin mRNA 表达，并降低蚊子的存活率。综上所述，这些数据表明间隙连接可能为杀虫剂的开发提供新的分子和生理靶标。
The yellow fever mosquito Aedes aegypti is an important vector of viral diseases that impact global health. Insecticides are typically used to manage mosquito populations, but the evolution of insecticide resistance is limiting their effectiveness. Thus, identifying new molecular and physiological targets in mosquitoes is needed to facilitate insecticide discovery and development. Here we test the hypothesis that gap junctions are valid molecular and physiological targets for new insecticides. Gap junctions are intercellular channels that mediate direct communication between neighboring cells and consist of evolutionarily distinct proteins in vertebrate (connexins) and invertebrate (innexins) animals. We show that the injection of pharmacological inhibitors of gap junctions (i.e., carbenoxolone, meclofenamic acid, or mefloquine) into the hemolymph of adult female mosquitoes elicits dose-dependent toxic effects, with mefloquine showing the greatest potency. In contrast, when applied topically to the cuticle, carbenoxolone was the only inhibitor to exhibit full efficacy. In vivo urine excretion assays demonstrate that both carbenoxolone and mefloquine inhibit the diuretic output of adult female mosquitoes, suggesting inhibition of excretory functions as part of their mechanism of action. When added to the rearing water of 1st instar larvae, carbenoxolone and meclofenamic acid both elicit dose-dependent toxic effects, with meclofenamic acid showing the greatest potency. Injecting a double-stranded RNA cocktail against innexins into the hemolymph of adult female mosquitoes knock down whole-animal innexin mRNA expression and decreases survival of the mosquitoes. Taken together these data indicate that gap junctions may provide novel molecular and physiological targets for the development of insecticides.