Martin Victor, Vale Carmen, Antelo Alvaro, Hirama Masahiro, Yamashita Shuji, Vieytes Mercedes R, Botana Luis M
Departamento de Farmacología, ‡Laboratorios Cifga, and §Departamento de Fisiología, Facultad de Veterinaria, Universidad de Santiago de Compostela , Campus Universitario s/n, 27002 Lugo, Spain.
Chem Res Toxicol. 2014 Aug 18;27(8):1387-400. doi: 10.1021/tx5000969. Epub 2014 Jul 15.
Ciguatoxins (CTXs) and maitotoxins (MTXs) are polyether ladder shaped toxins derived from the dinoflagellate Gambierdiscus toxicus. Despite the fact that MTXs are 3 times larger than CTXs, part of the structure of MTXs resembles that of CTXs. To date, the synthetic ciguatoxin, CTX 3C has been reported to activate voltage-gated sodium channels, whereas the main effect of MTX is inducing calcium influx into the cell leading to cell death. However, there is a lack of information regarding the effects of these toxins in a common cellular model. Here, in order to have an overview of the main effects of these toxins in mice cortical neurons, we examined the effects of MTX and the synthetic ciguatoxin CTX 3C on the main voltage dependent ion channels in neurons, sodium, potassium, and calcium channels as well as on membrane potential, cytosolic calcium concentration ([Ca(2+)]c), intracellular pH (pHi), and neuronal viability. Regarding voltage-gated ion channels, neither CTX 3C nor MTX affected voltage-gated calcium or potassium channels, but while CTX 3C had a large effect on voltage-gated sodium channels (VGSC) by shifting the activation and inactivation curves to more hyperpolarized potentials and decreasing peak sodium channel amplitude, MTX, at 5 nM, had no effect on VGSC activation and inactivation but decreased peak sodium current amplitude. Other major differences between both toxins were the massive calcium influx and intracellular acidification produced by MTX but not by CTX 3C. Indeed, the novel finding that MTX produces acidosis supports a pathway recently described in which MTX produces calcium influx via the sodium-hydrogen exchanger (NHX). For the first time, we found that VGSC blockers partially blocked the MTX-induced calcium influx, intracellular acidification, and protected against the short-term MTX-induced cytotoxicity. The results presented here provide the first report that shows the comparative effects of two prototypical ciguatera toxins, CTX 3C and MTX, in a neuronal model. We hypothesize that the analogies and differences in the bioactivity of these two toxins, produced by the same microorganism, may be strongly linked to their chemical structure.
雪卡毒素（CTXs）和刺尾鱼毒素（MTXs）是源自双鞭毛藻甘比毒藻的聚醚梯状毒素。尽管MTXs的大小是CTXs的3倍，但MTXs的部分结构与CTXs相似。迄今为止，已报道合成雪卡毒素CTX 3C可激活电压门控钠通道，而MTX的主要作用是诱导钙流入细胞导致细胞死亡。然而，关于这些毒素在常见细胞模型中的作用缺乏相关信息。在此，为了全面了解这些毒素对小鼠皮质神经元的主要影响，我们研究了MTX和合成雪卡毒素CTX 3C对神经元中主要电压依赖性离子通道（钠、钾和钙通道）以及膜电位、胞质钙浓度（[Ca(2+)]c）、细胞内pH值（pHi）和神经元活力的影响。关于电压门控离子通道，CTX 3C和MTX均未影响电压门控钙通道或钾通道，但CTX 3C通过将激活和失活曲线向更超极化电位移动并降低钠通道峰值幅度，对电压门控钠通道（VGSC）有很大影响，而5 nM的MTX对VGSC的激活和失活没有影响，但降低了钠电流峰值幅度。两种毒素之间的其他主要差异是MTX会导致大量钙流入和细胞内酸化，而CTX 3C则不会。事实上，MTX导致酸中毒这一新发现支持了最近描述的一条途径，即MTX通过钠氢交换体（NHX）产生钙流入。我们首次发现，VGSC阻滞剂部分阻断了MTX诱导的钙流入、细胞内酸化，并对MTX诱导的短期细胞毒性具有保护作用。此处呈现的结果首次报告了两种典型雪卡毒素CTX 3C和MTX在神经元模型中的比较作用。我们推测，由同一微生物产生的这两种毒素生物活性的相似性和差异可能与其化学结构密切相关。
