Recombinant PaurTx-3, a spider toxin, inhibits sodium channels and decreases membrane excitability in DRG neurons
Recombinant PaurTx-3, a spider toxin, inhibits sodium channels and decreases membrane excitability in DRG neurons
复制标题
重组 PaurTx-3 是一种蜘蛛毒素，可抑制钠通道并降低 DRG 神经元的膜兴奋性
DOI：
10.1016/j.bbrc.2020.09.103
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发表时间：
2020-12-17
影响因子：
3.1
通讯作者：
Liu, Zhonghua
中科院分区：
文献类型：
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作者：
Chen, Minzhi;Peng, Shuijiao;Liu, Zhonghua
电压门控钠通道对于动作电位的产生和传播至关重要。蜘蛛毒门控修饰毒素可以调节钠通道的门控机制，因此具有作为药物先导的潜力。在这里，我们建立了表达的门控修饰毒素PaurTx-3，钠通道抑制剂中发现的蜘蛛Phrixotrichus auratus的毒液。全细胞电压钳记录表明，重组PaurTx-3（rPaurTx-3）抑制Nav1.4，Nav1.5和Nav1.7电流的IC 50值分别为61 nM，72 nM和25 nM。此外，rPaurTx-3不可逆地抑制Nav1.7电流，但在用浴溶液洗涤后，在Nav1.4和Nav1.5中具有60-70%的回收率。rPaurTx-3还使电压依赖性稳态失活曲线超极化，并显著减缓了Nav1.7从快速失活的恢复。电流钳记录显示，rPaurTx-3抑制小DRG神经元的活动。rPaurTx-3的生物活性测定结果支持其在Nav1.7和小DRG神经元中的强效药理学作用。(C)2020爱思唯尔公司All rights reserved.
Voltage-gated sodium channels are critical for the generation and propagation of action potentials. Gating modifier toxins from spider venom can modulate the gating mechanism of sodium channels and thus have potential as drug leads. Here, we established expression of the gating modifier toxin PaurTx-3, a sodium channel inhibitor found in the venom of the spider Phrixotrichus auratus. Whole-cell voltage-clamp recordings indicated that recombinant PaurTx-3 (rPaurTx-3) inhibited Nav1.4, Nav1.5, and Nav1.7 currents with IC50 values of 61 nM, 72 nM, and 25 nM, respectively. Furthermore, rPaurTx-3 irreversibly inhibited Nav1.7 currents, but had 60-70% recovery in Nav1.4 and Nav1.5 after washing with a bath solution. rPaurTx-3 also hyperpolarized the voltage-dependent steady-state inactivation curve and significantly slowed recovery from fast inactivation of Nav1.7. Current-clamp recordings showed that rPaurTx-3 suppressed small DRG neuron activity. The biological activity assay findings for rPaurTx-3 support its potent pharmacological effect in Nav1.7 and small DRG neurons. (C) 2020 Elsevier Inc. All rights reserved.