Arena J P, Liu K K, Paress P S, Cully D F
Merck Sharp and Dohme Research Laboratories, Department of Biochemical Parasitology, Rahway, New Jersey 07065-0900.
Mol Pharmacol. 1991 Sep;40(3):368-74.
Avermectins are a family of potent broad-spectrum anthelmintic compounds, which bind with high affinity to membranes isolated from the free-living nematode Caenorhabditis elegans. Binding of avermectins is thought to modulate chloride channel activity, but the exact mechanism for anthelmintic activity remains to be determined. In this report, the properties of an avermectin-sensitive membrane current were evaluated in Xenopus laevis oocytes that were injected with poly(A)+ RNA from C. elegans. In such oocytes, avermectins increased inward membrane current at a holding potential of -80 mV. An avermectin analog without anthelmintic activity had no effect. Half-maximal activation of current was observed with 90 nM avermectin. The reversal potential for avermectin-sensitive current was -19.3 +/- 1.9 mV, and it shifted with external chloride, as expected for a chloride current. Avermectin increased membrane current in C. elegans-injected oocytes that were also injected with the Ca2+ chelator ethylene glycol bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid. The response to avermectin was greatest in the 1.0-2.5-kilobase class of size-fractionated C. elegans poly(A)+ RNA. Oocytes that responded to avermectin were insensitive to gamma-aminobutyric acid and the avermectin-induced current was blocked by picrotoxin.
阿维菌素是一类强效的广谱抗蠕虫化合物，它们与从自由生活的线虫秀丽隐杆线虫分离得到的膜具有高亲和力结合。阿维菌素的结合被认为可调节氯离子通道活性，但抗蠕虫活性的确切机制仍有待确定。在本报告中，在注射了来自秀丽隐杆线虫的聚腺苷酸加尾RNA的非洲爪蟾卵母细胞中评估了阿维菌素敏感膜电流的特性。在这类卵母细胞中，阿维菌素在 -80 mV的钳制电位下增加内向膜电流。一种没有抗蠕虫活性的阿维菌素类似物没有作用。在90 nM阿维菌素时观察到电流的半数最大激活。阿维菌素敏感电流的反转电位为 -19.3±1.9 mV，并且如氯离子电流所预期的那样，它随外部氯离子浓度而变化。阿维菌素在同时注射了钙离子螯合剂乙二醇双（β-氨基乙基醚）-N，N，N'，N'-四乙酸的注射了秀丽隐杆线虫RNA的卵母细胞中增加膜电流。在大小分级的秀丽隐杆线虫聚腺苷酸加尾RNA的1.0 - 2.5千碱基类别中，对阿维菌素的反应最大。对阿维菌素产生反应的卵母细胞对γ-氨基丁酸不敏感，并且阿维菌素诱导的电流被印防己毒素阻断。
