Two Novel Peptide Toxins from the Spider Cyriopagopus longipes Inhibit Tetrodotoxin-Sensitive Sodium Channels.
Two Novel Peptide Toxins from the Spider Cyriopagopus longipes Inhibit Tetrodotoxin-Sensitive Sodium Channels.
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来自长足蜘蛛的两种新型肽毒素抑制河豚毒素敏感的钠通道
DOI：
10.3390/toxins12090529
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发表时间：
2020-08-19
期刊：
影响因子：
4.2
通讯作者：
Liu Z
中科院分区：
文献类型：
--
作者：
Zhang Q;Si Y;Yang L;Wang L;Peng S;Chen Y;Chen M;Zhou X;Liu Z
钠通道在可兴奋组织（如神经、心肌和骨骼肌）中动作电位的产生和传播中起关键作用，并且是动物毒液中发现的毒素的主要靶标。在这里，两个新的肽毒素（Cl 6a和Cl 6 b）的蜘蛛Cyriopagopus longipes的毒液中分离和表征。C16 a和C16 b被证明是河豚毒素敏感性（TTX-S）钠通道的抑制剂，但不是TTX抗性钠通道的抑制剂。在研究的TTX-S通道中，Cl 6a和Cl 6 b以不可逆的方式显示出对NaV1.7的最高程度的抑制（半最大抑制浓度（IC 50）分别为11.0 ± 2.5 nM和18.8 ± 2.4 nM），该方式不改变通道活化、失活或再引发动力学。此外，NaV1.7/NaV1.8嵌合通道的分析揭示了Cl 6 b是位点4神经毒素。定点突变分析表明D816、V817和E818显著影响Cl 6 b-NaV 1.7相互作用的效力，表明这些残基可能直接影响NaV 1. 7与Cl 6 b的相互作用。两者合计，这两种新的肽毒素作为有效的和持续的NaV1.7阻滞剂，并可能在钠通道的药理学研究的潜力。
Sodium channels play a critical role in the generation and propagation of action potentials in excitable tissues, such as nerves, cardiac muscle, and skeletal muscle, and are the primary targets of toxins found in animal venoms. Here, two novel peptide toxins (Cl6a and Cl6b) were isolated from the venom of the spider Cyriopagopus longipes and characterized. Cl6a and Cl6b were shown to be inhibitors of tetrodotoxin-sensitive (TTX-S), but not TTX-resistant, sodium channels. Among the TTX-S channels investigated, Cl6a and Cl6b showed the highest degree of inhibition against NaV1.7 (half-maximal inhibitory concentration (IC50) of 11.0 ± 2.5 nM and 18.8 ± 2.4 nM, respectively) in an irreversible manner that does not alter channel activation, inactivation, or repriming kinetics. Moreover, analysis of NaV1.7/NaV1.8 chimeric channels revealed that Cl6b is a site 4 neurotoxin. Site-directed mutagenesis analysis indicated that D816, V817, and E818 observably affected the efficacy of the Cl6b-NaV1.7 interaction, suggesting that these residues might directly affect the interaction of NaV1.7 with Cl6b. Taken together, these two novel peptide toxins act as potent and sustained NaV1.7 blockers and may have potential in the pharmacological study of sodium channels.
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影响因子：
56.9
作者：
Shen, Huaizong;Liu, Dongliang;Yan, Nieng
通讯作者：
Yan, Nieng
影响因子：
5.6
作者：
Gonçalves TC;Benoit E;Partiseti M;Servent D
通讯作者：
Servent D
影响因子：
64.8
作者：
Osteen JD;Herzig V;Gilchrist J;Emrick JJ;Zhang C;Wang X;Castro J;Garcia-Caraballo S;Grundy L;Rychkov GY;Weyer AD;Dekan Z;Undheim EA;Alewood P;Stucky CL;Brierley SM;Basbaum AI;Bosmans F;King GF;Julius D
通讯作者：
Julius D
影响因子：
7.3
作者：
Ruiz, Manuel de Lera;Kraus, Richard L.
通讯作者：
Kraus, Richard L.
影响因子：
4.2
作者：
Herzig V;King GF
通讯作者：
King GF