A quantitative and comparative study of the effects of a synthetic ciguatoxin CTX3C on the kinetic properties of voltage‐dependent sodium channels
A quantitative and comparative study of the effects of a synthetic ciguatoxin CTX3C on the kinetic properties of voltage‐dependent sodium channels
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合成雪卡毒素 CTX3C 对电压依赖性钠定量通道动力学特性影响的比较研究
DOI：
10.1038/sj.bjp.0705852
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发表时间：
2004
影响因子：
7.3
通讯作者：
M. Hirama*
中科院分区：
文献类型：
--
作者：
K. Yamaoka;M. Inoue;H. Miyahara;K. Miyazaki;M. Hirama*
已知雪卡毒素（CTXs）与电压依赖性Na通道的受体5位点结合，但毒素的生理效应尚不清楚。在这项研究中，我们研究了一种ciguatoxin同源物（CTX3C）对三种不同的Na通道亚型rNav1.2、rNav1.4和rNav1.5的影响，这些亚型在HEK293细胞中短暂表达。毒素（1.0 μmol l−1）使激活电位（激活曲线V1/2）向负方向移动了4 ~ 9 mV，并使斜率因子(k)从8 mV增加到9 ~ 12 mV（表明激活曲线陡度降低），从而导致所有Na通道同工型的阈值电位发生了30 mV的超极化移动。毒素（1.0 μmol l−1）显著加速rNav1.2异型体的峰时电流，从0.62 ms提高到0.52 ms。较高剂量的毒素（3-10 μmol l−1）进一步降低了rNav1.4和rNav1.5的峰时电流。即使在较高剂量的CTX3C下，毒素效应对−20 mV下INa的衰减也不存在或很微弱。毒素（1 μmol l−1）使各亚型的失活电位（失活曲线V1/2）向负方向移动15 ~ 18 mV。1.0 μmol l−1 CTX3C对三种同工异构体的I-V曲线（−20 mV）的最大值均有相似程度的抑制（80-85%）。高剂量CTX3C （10 μmol l−1）进一步抑制了INa，达到对照的61-72%。在1.0 μmol l−1 CTX3C的存在下，中等持续时间（500 ms）的去极化预脉冲诱导的缓慢失活恢复明显延迟，单指数恢复时间常数分别从rNav1.2、rNav1.4和rNav1.5的38±8 ms增加到588±151 ms （n=5）、53±6 ms增加到338±85 ms （n=4）和23±3 ms增加到232±117 ms （n=3）。CTX3C对钠通道具有多模态作用，同时具有刺激和抑制作用，这可能是由于这种跨膜毒素的大分子尺寸（长度为3nm）和亲脂性。
Ciguatoxins (CTXs) are known to bind to receptor site 5 of the voltage‐dependent Na channel, but the toxin's physiological effects are poorly understood. In this study, we investigated the effects of a ciguatoxin congener (CTX3C) on three different Na‐channel isoforms, rNav1.2, rNav1.4, and rNav1.5, which were transiently expressed in HEK293 cells. The toxin (1.0 μmol l−1) shifted the activation potential (V1/2 of activation curve) in the negative direction by 4–9 mV and increased the slope factor (k) from 8 mV to between 9 and 12 mV (indicative of decreased steepness of the activation curve), thereby resulting in a hyperpolarizing shift of the threshold potential by 30 mV for all Na channel isoforms. The toxin (1.0 μmol l−1) significantly accelerated the time‐to‐peak current from 0.62 to 0.52 ms in isoform rNav1.2. Higher doses of the toxin (3–10 μmol l−1) additionally decreased time‐to‐peak current in rNav1.4 and rNav1.5. A toxin effect on decay of INa at −20 mV was either absent or marginal even at relatively high doses of CTX3C. The toxin (1 μmol l−1) shifted the inactivation potential (V1/2 of inactivation curve) in the negative direction by 15–18 mV in all isoforms. INa maxima of the I–V curve (at −20 mV) were suppressed by application of 1.0 μmol l−1 CTX3C to a similar extent (80–85% of the control) in all the three isoforms. Higher doses of CTX3C up to 10 μmol l−1 further suppressed INa to 61–72% of the control. Recovery from slow inactivation induced by a depolarizing prepulse of intermediate duration (500 ms) was dramatically delayed in the presence of 1.0 μmol l−1 CTX3C, as time constants describing the monoexponential recovery were increased from 38±8 to 588±151 ms (n=5), 53±6 to 338±85 ms (n=4), and 23±3 to 232±117 ms (n=3) in rNav1.2, rNav1.4, and rNav1.5, respectively. CTX3C exerted multimodal effects on sodium channels, with simultaneous stimulatory and inhibitory aspects, probably due to the large molecular size (3 nm in length) and lipophilicity of this membrane‐spanning toxin.
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DOI：
10.1073/pnas.89.22.10910
发表时间：
1992-11-15
影响因子：
11.1
作者：
WEST, JW;PATTON, DE;CATTERALL, WA
通讯作者：
CATTERALL, WA
DOI：
--
发表时间：
1994-08
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
V. Trainer;D. Baden;W. Catterall
通讯作者：
V. Trainer;D. Baden;W. Catterall
DOI：
--
发表时间：
1998-02
期刊：
The Journal of pharmacology and experimental therapeutics
影响因子：
--
作者：
G. Jeglitsch;K. Rein;D. Baden;David John Adams
通讯作者：
G. Jeglitsch;K. Rein;D. Baden;David John Adams
影响因子：
3.4
作者：
O'Reilly, JP;Wang, SY;Wang, GK
通讯作者：
Wang, GK
影响因子：
3.4
作者：
Wang, SY;Wang, GK
通讯作者：
Wang, GK