Four novel tarantula toxins as selective modulators of voltage-gated sodium channel subtypes
Four novel tarantula toxins as selective modulators of voltage-gated sodium channel subtypes
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DOI：
10.1124/mol.105.015941
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发表时间：
2006-02-01
影响因子：
3.6
通讯作者：
Tytgat, J
中科院分区：
文献类型：
--
作者：
Bosmans, F;Rash, L;Tytgat, J
从狼蛛毒液中分离到4种作用于电压门控性钠通道的新的多肽毒素：角颈鹿的角鱼毒素1、2和3(CcoTx1、CcoTx2和CcoTx3)和金鱼的鞭毛虫毒素3(PaurTx3)。通过对非洲爪哇卵母细胞表达的6种克隆电压门控钠通道亚型(Na(V)1.1/beta(1)，N(V)1.2/beta 1，Na(V)1.3/beta(1)，Na(V)1.4/beta(1)，Na(V)1.5/beta(1)，Na(V)1.8/beta(1))的电生理测量，研究了这些新毒素的药理特征。这些新的毒素调节电压门控钠通道的特性类似于典型的门控调节剂毒素，既引起门控动力学的去极化转变，又通过阻断钠电流的内向分量。PaurTx3是迄今为止所描述的最有效的电压门控钠通道的多肽调节剂之一，它调节Na(V)1.2，其IC50值为0.6+/-0.1 nM。除了仅受CcoTx2影响的Na(V)1.3外，CcoTx1和CcoTx2是中枢不同电压门控钠通道亚型的有效调节剂。CcoTx3的效力较低，尽管这种毒素似乎对河豚毒素抗性通道亚型Na(V)1.5/beta(1)更具选择性(IC50=447+/-32 nM)。除了这些结果，分子模拟表明毒素表面的细微差异可能与它们不同的药理特征有关。此外，对这些毒素和其他结构上相关的三二硫化蜘蛛毒素的进化轨迹分析为探索毒素-通道相互作用和未来的结构-功能研究提供了线索。
Four novel peptide toxins that act on voltage-gated sodium channels have been isolated from tarantula venoms: ceratotoxins 1, 2, and 3 (CcoTx1, CcoTx2, and CcoTx3) from Ceratogyrus cornuatus and phrixotoxin 3 (PaurTx3) from Phrixotrichus auratus. The pharmacological profiles of these new toxins were characterized by electrophysiological measurements on six cloned voltage-gated sodium channel subtypes expressed in Xenopus laevis oocytes (Na(v)1.1/beta(1), N (v)1.2/beta 1, Na(v)1.3/beta(1), Na(v)1.4/beta(1), Na(v)1.5/beta(1), and Na(v)1.8/beta(1)). These novel toxins modulate voltage-gated sodium channels with properties similar to those of typical gating-modifier toxins, both by causing a depolarizing shift in gating kinetics and by blocking the inward component of the sodium current. PaurTx3 is one of the most potent peptide modulators of voltage-gated sodium channels described thus far from spider venom, modulating Na(v)1.2 with an IC50 value of 0.6 +/- 0.1 nM. CcoTx1 and CcoTx2, differing by only one amino acid, are potent modulators of different voltage-gated sodium channel subtypes from the central nervous system, except for Na(v)1.3, which is only affected by CcoTx2. The potency of CcoTx3 is lower, although this toxin seems to be more selective for the tetrodotoxin-resistant channel subtype Na(v)1.5/beta(1) (IC50 = 447 +/- 32 nM). In addition to these results, molecular modeling indicates that subtle differences in toxin surfaces may relate to their different pharmacological profiles. Furthermore, an evolutionary trace analysis of these toxins and other structurally related three-disulfide spider toxins provides clues for the exploration of toxin-channel interaction and future structure-function research.