Abalis I M, Eldefrawi A T, Eldefrawi M E
Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore.
J Biochem Toxicol. 1986 Mar;1(1):69-82. doi: 10.1002/jbt.2570010108.
The interaction of avermectin B1a (AVM) with the gamma-aminobutyric acid (GABA) receptor of rat brain was studied using radioactive ligand binding and tracer ion flux assays. Avermectin potentiated the binding of [3H]flunitrazepam and inhibited the binding of both [3H]muscimol and [35S]t-butylbicyclophosphorothionate to the GABAA receptor. Inhibition of muscimol binding by AVM suggested competitive displacement. Two kinds of 36chloride (Cl) flux were studied. The 36Cl efflux from preloaded microsacs was potentiated by AVM and was highly inhibited by the Cl-channel blocker 4,4'-diisothiocyano-2,2'-stilbenedisulfonic acid (DIDS). However, it was not potentiated by GABA nor was it sensitive to the convulsants picrotoxin or bicuculline. On the other hand, 36Cl-influx measurement in a different microsac preparation of rat brain was very sensitive to GABA and other GABA-ergic drugs. Avermectin induced 36Cl influx into these microsacs in a dose-dependent manner, but to only 35% of the maximal influx induced by GABA. The AVM-induced 36Cl influx was totally blocked by bicuculline. It is suggested that AVM opens the GABAA-receptor Cl channel by binding to the GABA recognition site and acting as a partial receptor agonist, and also opens a voltage-dependent Cl channel which is totally insensitive to GABA but is very sensitive to DIDS.
采用放射性配体结合法和示踪离子通量分析法研究了阿维菌素B1a（AVM）与大鼠脑γ-氨基丁酸（GABA）受体的相互作用。阿维菌素增强了[3H]氟硝西泮的结合，并抑制了[3H]蝇蕈醇和[35S]叔丁基双环磷硫代酸酯与GABAA受体的结合。AVM对蝇蕈醇结合的抑制表明存在竞争性置换。研究了两种36氯（Cl）通量。AVM增强了预加载微囊的36Cl外流，且被Cl通道阻滞剂4,4'-二异硫氰酸-2,2'-二苯乙烯二磺酸（DIDS）高度抑制。然而，它不受GABA增强，对惊厥剂印防己毒素或荷包牡丹碱也不敏感。另一方面，在大鼠脑不同微囊制剂中进行的36Cl内流测量对GABA和其他GABA能药物非常敏感。阿维菌素以剂量依赖性方式诱导36Cl流入这些微囊，但仅为GABA诱导的最大内流的35%。AVM诱导的36Cl内流被荷包牡丹碱完全阻断。提示AVM通过与GABA识别位点结合并作为部分受体激动剂打开GABAA受体Cl通道，还打开了一个电压依赖性Cl通道，该通道对GABA完全不敏感，但对DIDS非常敏感。
