Neurotoxic implications of the agonistic action of CS-syndrome pyrethroids on the N-type Cav2.2. calcium channel
Neurotoxic implications of the agonistic action of CS-syndrome pyrethroids on the N-type Cav2.2. calcium channel
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DOI：
10.1002/ps.1573
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发表时间：
2008-06-01
影响因子：
4.1
通讯作者：
Symington, Steven B.
中科院分区：
文献类型：
--
作者：
Clark, J. Marshall;Symington, Steven B.
背景技术背景：先前已证明顺式菊酯（T综合征）和溴氰菊酯（CS综合征）拟除虫菊酯可增加膜去极化和钙内流，但仅溴氰菊酯可增加大鼠脑突触体的Ca2+依赖性神经递质释放。溴氰菊酯的作用被ω-芋螺毒素GVIA阻断，描绘了N型Ca（v）2.2通道的单独作用，这与神经递质的体内释放一致。据推测，其他CS综合征拟除虫菊酯将引起类似的行动在突触前nerve terminals. RESULTS：九个额外的拟除虫菊酯进行了类似的检查，这些数据被用于聚类分析。具有α-氰基基团的CS综合征拟除虫菊酯，氯氰菊酯，溴氰菊酯和顺式氰戊菊酯，均引起Ca2+内流和神经递质释放，并与其他两种α-氰基拟除虫菊酯，氟氯氰菊酯和三氟氯氰菊酯聚集，它们具有相同的作用。T综合征拟除虫菊酯、生物丙烯菊酯、顺式菊酯和甲氰菊酯没有这些作用，并与两种非α-氰基拟除虫菊酯、七氟菊酯和联苯菊酯聚类，后者同样没有引起这些作用。溴氰菊酯降低了异源表达的野生型Ca（v）2.2的峰电流，增加了T422E Ca（v）2.2的峰电流，并且对T422E Cav2.2的效力是野生型通道的20倍，表明Ca（v）2.2的永久磷酸化形式是首选靶点。Ca（v）2.2直接被溴氰菊酯修饰，但产生的扰动取决于其磷酸化状态。目前的研究结果可能提供了一个不同的毒性综合征产生的这些结构不同的拟除虫菊酯的部分解释。(C)2008化学工业协会。
BACKGROUND: Cismethrin (T-syndrome) and deltamethrin (CS-syndrome) pyrethroids have been previously shown to increase membrane depolarization and calcium influx, but only deltamethrin increased Ca2+-dependent neurotransmitter release from rat brain synaptosomes. Deltamethrin's action was blocked by omega-conotoxin GVIA, delineating a separate action at N-type Ca(v)2.2 channels that is consistent with the in vivo release of neurotransmitter. It is hypothesized that other CS-syndrome pyrethroids will elicit similar actions at presynaptic nerve terminals.RESULTS: Nine additional pyrethroids were similarly examined, and these data were used in a cluster analysis. CS-syndrome pyrethroids that possessed alpha-cyano groups, cypermethrin, deltamethrin and esfenvalerate, all caused Ca2+ influx and neurotransmitter release and clustered with two other a-cyano pyrethroids, cyfluthrin and cyhalothrin, that shared these same actions. T-syndrome pyrethroids, bioallethrin, cismethrin and fenpropathrin, did not share these actions and clustered with two non-alpha-cyano pyrethroids, tefluthin and bifenthrin, which likewise did not elicit these actions. Deltamethrin reduced peak current of heterologously expressed wild-type Ca(v)2.2, increased peak current of T422E Ca(v)2.2 and was 20-fold more potent on T422E Cav2.2 than on wild-type channels, indicating that the permanently phosphorylated form of Ca(v)2.2 is the preferred target.CONCLUSIONS: Ca(v)2.2 is directly modified by deltamethrin, but the resulting perturbation is dependent upon its phosphorylation state. The present findings may provide a partial explanation for the different toxic syndromes produced by these structurally distinct pyrethroids. (C) 2008 Society of Chemical Industry.