The insecticide chlorantraniliprole is a weak activator of mammalian skeletal ryanodine receptor/Ca2+ release channel
The insecticide chlorantraniliprole is a weak activator of mammalian skeletal ryanodine receptor/Ca2+ release channel
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杀虫剂氯虫苯甲酰胺是哺乳动物骨骼兰尼碱受体/Ca2 释放通道的弱激活剂
DOI：
10.1016/j.bbrc.2018.11.180
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发表时间：
2019-01-08
影响因子：
3.1
通讯作者：
Yin, Chang-Cheng
中科院分区：
文献类型：
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作者：
Chen, Jian;Xue, Liang;Yin, Chang-Cheng
氯虫苯甲酰胺探针（Chlorantraniliprobe，Chlo）是一种高效的杀虫剂，它通过ryanodine受体（RyRs）诱导昆虫细胞内Ca ~（2+）释放，破坏昆虫细胞内Ca ~（2+）的稳态。Chlo对昆虫是致命的，但对哺乳动物的毒性很低。在这项研究中，我们研究了Chlo对哺乳动物骨骼肌RyR 1的影响。Ca ~（2+）释放实验表明，高浓度Chlo通过RyR 1通道促进肌浆网Ca ~（2+）释放。对纯化的RyR 1通道的单通道记录表明，Chlo激活了RyR 1通道，增加了通道开放概率P-o，缩短了通道平均关闭时间Tc，但不改变通道平均开放时间T-o，表明Chlo使关闭的RyR 1通道不稳定，使通道易于开放。Chlo对RyR 1的解离常数Kd值为微摩尔级，约为昆虫RyR的100倍。开放状态的Kd值小于RyR 1通道的关闭/阻断状态。在通道激活剂或抑制剂/阻断剂存在下，最大结合容量B-max没有变化。我们的研究结果表明，杀虫剂Chlo是哺乳动物RyR 1的弱激活剂。它可以与哺乳动物RyR 1相互作用并激活RyR 1通道，但与昆虫RyR相比亲和力低得多; Chlo具有不同于所有已知RyR通道调节剂的结合位点，代表了一种新型的RyR通道调节剂。我们的数据提供了生物化学和药理学的见解，其高度特异性昆虫RyR和高选择性的中毒昆虫哺乳动物。(C)2018爱思唯尔公司All rights reserved.
Chlorantraniliprobe (Chlo), a potent insecticide, demolishes intracellular Ca2+ homeostasis of insects by inducing uncontrolled Ca2+ release through ryanodine receptors (RyRs). Chlo is lethal to insects but has low toxicity to mammals. In this study, we investigated the effects of Chlo on RyR1 from mammalian skeletal muscle. Ca2+ release assay indicated that Chlo at high concentrations promoted Ca2+ release from sarcoplasmic reticulum through RyR1 channels. Single channel recording of purified RyR1 showed that Chlo activated RyR1 channel, increased channel open probability P-o, reduced channel mean close time T-c, but did not change the channel mean open time T-o, suggesting that Chlo destabilized the closed RyR1 channel, rendered the channel easy to open. The dissociation constant K-d values of Chlo for RyR1 were of micromolar level, approximately 100-fold larger than that for insect RyR. The K-d values were smaller for open states than for closed/blocked states of the RyR1 channel. The maximal binding capacity B-max did not change in the presence of either channel activators or inhibitors/blockers. Our results demonstrate that the insecticide Chlo is a weak activator of mammalian RyR1. It can interact with mammalian RyR1 and activate RyR1 channel but with much lower affinity compared with insect RyR; Chlo has a binding site distinct from all known RyR channel modulators and represents a novel type of RyR channel modulator. Our data provide biochemical and pharmacological insights into its high specificity to insect RyR and high selectivity of poisoning to insects over mammals. (C) 2018 Elsevier Inc. All rights reserved.