Clioquinol and pyrithione activate TRPA1 by increasing intracellular Zn2+
Clioquinol and pyrithione activate TRPA1 by increasing intracellular Zn2+
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DOI：
10.1073/pnas.0812675106
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发表时间：
2009-05-19
影响因子：
11.1
通讯作者：
Bevan, Stuart
中科院分区：
文献类型：
--
作者：
Andersson, David A.;Gentry, Clive;Bevan, Stuart
抗真菌和阿米巴杀灭药物CLOQOL(CQ)因与亚急性脊髓视神经病(SMON)流行有关而被召回市场。CLOQOL通过作为铜/锌的螯合剂和离子载体发挥其抗寄生虫作用。在这里，我们证明了局部注射CQ通过涉及TRPA1的机制在小鼠中产生机械性痛敏和冷过敏。我们还发现CQ以一种依赖于锌离子的方式激活TRPA1。使用不同的锌离子载体--吡硫锌(ZnPy)，我们证明了细胞内低纳摩尔浓度的锌离子([Zn2+](I))可以刺激TRPA1。将锌离子直接作用于细胞内面，可激活TRPA1，其EC50值为7.5+/-1 NM。TRPA1在伤害性背根神经节(DRG)神经元亚群中表达，是环境刺激物和氧化剂的感觉受体。利用培养的野生型和TRPA1缺陷型小鼠的DRG神经元，我们证明了TRPA1是DRG神经元中升高的[Zn2+](I)的主要兴奋受体。综上所述，我们发现TRPA1是细胞内锌离子的感受器，而锌离子载体，如CQ和ZnPy，通过增加[Zn2+](I)来激活TRPA1。我们还在体内证明了CQ引起的机械性痛敏和冷痛需要TRPA1。
The antifungal and amoebicidal drug clioquinol (CQ) was withdrawn from the market when it was linked to an epidemic of subacute myelo-optico-neuropathy (SMON). Clioquinol exerts its anti-parasitic actions by acting as a Cu/Zn chelator and ionophore. Here we show that local injections of CQ produce mechanical hyperalgesia and cold hypersensitivity through a mechanism involving TRPA1 in mice. We also show that CQ activates TRPA1 in a Zn2+-dependent manner. Using a different Zn2+-ionophore, zinc pyrithione (ZnPy), we demonstrate that low, nanomolar concentrations of intracellular Zn2+ ([Zn2+](i)) stimulate TRPA1. Direct application of Zn2+ to the intracellular face of excised, inside-out patches activates TRPA1 with an EC50 value of 7.5 +/- 1 nM. TRPA1 is expressed in a subpopulation of nociceptive dorsal root ganglion (DRG) neurons, where it acts as a sensory receptor for environmental irritants and oxidants. Using cultured DRG neurons from wild-type and TRPA1-deficient mice, we demonstrate that TRPA1 is the principal excitatory receptor for increased [Zn2+](i) in DRG neurons. In conclusion, we have discovered that TRPA1 acts a sensor of intracellular Zn2+, and that Zn2+ ionophores, such as CQ and ZnPy, activate TRPA1 by increasing [Zn2+](i). We also demonstrate that CQ-evoked mechanical hyperalgesia and cold allodynia require TRPA1 in vivo.