Multiple sodium channel isoforms mediate the pathological effects of Pacific ciguatoxin-1.
Multiple sodium channel isoforms mediate the pathological effects of Pacific ciguatoxin-1.
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DOI：
10.1038/srep42810
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发表时间：
2017-02-22
影响因子：
4.6
通讯作者：
Vetter I
中科院分区：
文献类型：
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作者：
Inserra MC;Israel MR;Caldwell A;Castro J;Deuis JR;Harrington AM;Keramidas A;Garcia-Caraballo S;Maddern J;Erickson A;Grundy L;Rychkov GY;Zimmermann K;Lewis RJ;Brierley SM;Vetter I
人类中毒的海鲜毒素雪卡毒素，甲藻聚醚激活电压门控钠通道（NaV），导致雪卡毒素，一种疾病的特点是胃肠道和神经系统紊乱。我们使用成像和电生理方法评估了最有效的同源物太平洋雪卡毒素-1（P-CTX-1）对NaV1.1-1.9的活性。虽然P-CTX-1基本上是一种非选择性NaV毒素，并在所有NaV亚型中将电压依赖性激活转移到更高的超极化电位，但仅在NaV 1.8处观察到失活时间常数增加，而NaV 1.7的电导-电压曲线的斜率因子显著增加，NaV 1.6的峰值电流显著增加。因此，在分别对NaV1.8和河豚毒素敏感亚型NaV1.7和NaV1.6进行药理学抑制后，P-CTX-1诱导的内脏和皮肤疼痛行为显著降低。使用小鼠皮肤和内脏单纤维记录证实，这些亚型对外周C纤维和A纤维感觉神经元兴奋性的贡献反映了外周感觉神经元中NaV亚型的表达模式及其对膜去极化、动作电位的贡献启动和传播。
Human intoxication with the seafood poison ciguatoxin, a dinoflagellate polyether that activates voltage-gated sodium channels (NaV), causes ciguatera, a disease characterised by gastrointestinal and neurological disturbances. We assessed the activity of the most potent congener, Pacific ciguatoxin-1 (P-CTX-1), on NaV1.1–1.9 using imaging and electrophysiological approaches. Although P-CTX-1 is essentially a non-selective NaV toxin and shifted the voltage-dependence of activation to more hyperpolarising potentials at all NaV subtypes, an increase in the inactivation time constant was observed only at NaV1.8, while the slope factor of the conductance-voltage curves was significantly increased for NaV1.7 and peak current was significantly increased for NaV1.6. Accordingly, P-CTX-1-induced visceral and cutaneous pain behaviours were significantly decreased after pharmacological inhibition of NaV1.8 and the tetrodotoxin-sensitive isoforms NaV1.7 and NaV1.6, respectively. The contribution of these isoforms to excitability of peripheral C- and A-fibre sensory neurons, confirmed using murine skin and visceral single-fibre recordings, reflects the expression pattern of NaV isoforms in peripheral sensory neurons and their contribution to membrane depolarisation, action potential initiation and propagation.