Abstract
Zinc is an essential biological trace element. It is required for the structure or function of over 300 proteins, and it is increasingly recognized for its role in cell signaling. However, high concentrations of zinc have cytotoxic effects, and overexposure to zinc can cause pain and inflammation through unknown mechanisms. Here we show that zinc excites nociceptive somatosensory neurons and causes nociception in mice through TRPA1, a cation channel previously shown to mediate the pungency of wasabi and cinnamon through cysteine modification. Zinc activates TRPA1 through a unique mechanism that requires zinc influx through TRPA1 channels and subsequent activation via specific intracellular cysteine and histidine residues. TRPA1 is highly sensitive to intracellular zinc, as low nanomolar concentrations activate TRPA1 and modulate its sensitivity. These findings identify TRPA1 as an important target for the sensory effects of zinc and support an emerging role for zinc as a signaling molecule that can modulate sensory transmission.
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Acknowledgements
We thank J. Mathur, T. Earley, J. Watson and M. Garrett for excellent technical support, T. Miyamoto (The Scripps Research Institute) and B. Xiao (The Scripps Research Institute) for supplying mutant TRPA1 constructs, and T. Jegla and members of the Patapoutian lab for helpful discussions. We thank D. Corey (Harvard Medical School) for the Trpa1−/− mice. We also thank the following individuals for generously sharing reagents: M. Caterina (Johns Hopkins University) for rat TRPV1 and N. Prevarskaya (Universite des Sciences et Technologies de Lille) for human TRPM8. This research was supported by the US National Institutes of Health and the Novartis Research Foundation.
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Hu, H., Bandell, M., Petrus, M. et al. Zinc activates damage-sensing TRPA1 ion channels. Nat Chem Biol 5, 183–190 (2009). https://doi.org/10.1038/nchembio.146
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DOI: https://doi.org/10.1038/nchembio.146
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