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Zinc activates damage-sensing TRPA1 ion channels

Nature Chemical Biology volume 5, pages 183–190 (2009)Cite this article

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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Figure 1: Zinc activates sensory neurons through TRPA1.
Figure 2: TRPA1 mediates zinc-induced nocifensive behavior.
Figure 3: Zinc activates TRPA1 through intracellular sites.
Figure 4: Zinc permeation through TRPA1 is required for activation by extracellular zinc.
Figure 5: Role of cysteine and histidine residues in TRPA1 activation by zinc.
Figure 6: H983A and C641S C1021S double mutant exhibit decreased intracellular zinc sensitivity.

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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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  1. Hongzhen Hu and Michael Bandell: These authors contributed equally to this work.

Authors and Affiliations

  1. Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, 92121, California, USA

    Hongzhen Hu, Michael Bandell, Matt J Petrus & Ardem Patapoutian

  2. Department of Neuroscience, The Ohio State University, 333 West 10th Avenue, Columbus, 43210, Ohio, USA

    Michael X Zhu

  3. Department of Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, 92037, California, USA

    Ardem Patapoutian

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Correspondence to Ardem Patapoutian.

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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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