期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2009
卷号：106
期号：20
页码：8374-8379
DOI：10.1073/pnas.0812675106
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：The antifungal and amoebicidal drug clioquinol (CQ) was withdrawn from the market when it was linked to an epidemic of subacute myelo-optico-neuropathy (SMON).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.
