Synergistic and antagonistic interactions between tetrodotoxin and mu-conotoxin in blocking voltage-gated sodium channels.
Synergistic and antagonistic interactions between tetrodotoxin and mu-conotoxin in blocking voltage-gated sodium channels.
复制标题
DOI：
10.4161/chan.3.1.7500
复制
发表时间：
2009-01
期刊：
影响因子：
--
通讯作者：
Yoshikami D
中科院分区：
文献类型：
--
作者：
Zhang MM;McArthur JR;Azam L;Bulaj G;Olivera BM;French RJ;Yoshikami D
河豚毒素（TTX）是电压门控钠通道（NaVs）的典型配体。与TTX一样，μ-芋螺毒素肽是孔阻断剂，并且两种毒素都有助于定义NaV的神经毒素受体位点1的性质。在这里，我们报告了意想不到的结果，表明最近发现的μ-芋螺毒素KIIIA和TTX可以同时结合位点1并协同作用。将饱和浓度的肽应用于表达脑NaV1.2的电压钳位爪蟾卵母细胞，以及脂质双层中脑通道的单通道记录的结果表明，KIIIA或其类似物KIIIA[K7 A]部分阻断，残留电流可以被TTX完全阻断。此外，TTX和肽的阻断动力学各自受到先前存在的其他毒素的影响。例如，结合的肽减慢TTX的后续结合（拮抗相互作用），并且当两种毒素结合时减慢TTX解离（阻断的协同效应）。由毒素的联合作用产生的总体功能后果取决于这些相反作用之间的定量平衡。结果使我们假设在双配体NaV复合物中，TTX结合在肽和选择性过滤器之间。这些观察结果完善了我们对站点1的看法，并为NaV药理学开辟了新的可能性。
Tetrodotoxin (TTX) is the quintessential ligand of voltage-gated sodium channels (NaVs). Like TTX, μ-conotoxin peptides are pore blockers, and both toxins have helped to define the properties of neurotoxin receptor Site 1 of NaVs. Here, we report unexpected results showing that the recently discovered μ-conotoxin KIIIA and TTX can simultaneously bind to Site 1 and act in concert. Results with saturating concentrations of peptide applied to voltage-clamped Xenopus oocytes expressing brain NaV1.2, and single-channel recordings from brain channels in lipid bilayers, show that KIIIA or its analog, KIIIA[K7A], block partially, with a residual current that can be completely blocked by TTX. In addition, the kinetics of block by TTX and peptide are each affected by the prior presence of the other toxin. For example, bound peptide slows subsequent binding of TTX (an antagonistic interaction) and slows TTX dissociation when both toxins are bound (a synergistic effect on block). The overall functional consequence resulting from the combined action of the toxins depends on the quantitative balance between these opposing actions. The results lead us to postulate that in the bi-liganded NaV complex, TTX is bound between the peptide and the selectivity filter. These observations refine our view of Site 1 and open new possibilities in NaV pharmacology.
登录
查看更多内容
DOI：
10.1002/neu.20094
发表时间：
2004-10-01
期刊：
JOURNAL OF NEUROBIOLOGY
影响因子：
--
作者：
Wood, JN;Boorman, JP;Baker, MD
通讯作者：
Baker, MD
影响因子：
2.9
作者：
BECKER, S;PRUSAKSOCHACZEWSKI, E;FRENCH, RJ
通讯作者：
FRENCH, RJ
影响因子：
3.3
作者：
Choudhary, Gaurav;Aliste, Marcela P.;Dudley, Samuel C., Jr.
通讯作者：
Dudley, Samuel C., Jr.
影响因子：
16.2
作者：
French, RJ;PrusakSochaczewski, E;Horn, R
通讯作者：
Horn, R
影响因子：
2.9
作者：
Bulaj, G;West, PJ;Olivera, BM
通讯作者：
Olivera, BM