Spider toxins activate the capsaicin receptor to produce inflammatory pain (original) (raw)
- Letter
- Published: 09 November 2006
- Sharleen Zhou2,
- Rebecca Piskorowski3 nAff5,
- Tetsuro Nikai4,
- Ellen A. Lumpkin3 nAff6,
- Allan I. Basbaum4,
- David King2 &
- …
- David Julius1
Nature volume 444, pages 208–212 (2006)Cite this article
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Abstract
Bites and stings from venomous creatures can produce pain and inflammation as part of their defensive strategy to ward off predators or competitors1,2. Molecules accounting for lethal effects of venoms have been extensively characterized, but less is known about the mechanisms by which they produce pain. Venoms from spiders, snakes, cone snails or scorpions contain a pharmacopoeia of peptide toxins that block receptor or channel activation as a means of producing shock, paralysis or death3,4,5. We examined whether these venoms also contain toxins that activate (rather than inhibit) excitatory channels on somatosensory neurons to produce a noxious sensation in mammals. Here we show that venom from a tarantula that is native to the West Indies contains three inhibitor cysteine knot (ICK) peptides that target the capsaicin receptor (TRPV1), an excitatory channel expressed by sensory neurons of the pain pathway6. In contrast with the predominant role of ICK toxins as channel inhibitors5,7, these previously unknown ‘vanillotoxins’ function as TRPV1 agonists, providing new tools for understanding mechanisms of TRP channel gating. Some vanillotoxins also inhibit voltage-gated potassium channels, supporting potential similarities between TRP and voltage-gated channel structures. TRP channels can now be included among the targets of peptide toxins, showing that animals, like plants (for example, chilli peppers), avert predators by activating TRP channels on sensory nerve fibres to elicit pain and inflammation.
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Acknowledgements
We thank D. Minor and members of his laboratory for Kv4.2 and Kchip complementary RNAs and advice with chromatographic methods; D. Clapham and R. Aldrich for providing TRPV3 and Kv2.1 plasmids, respectively; K. Shokat and J. Blethrow for initial help with mass spectrometry; members of the Julius laboratory for discussions; and R. Nicoll, R. Edwards and H. Chuang for critical reading of the manuscript. This work was supported by NIH grants (to D.J., A.I.B. and E.A.L.) and by postdoctoral fellowships from the Swiss National Science Foundation, Novartis Stiftung, and the International Human Frontier Science Program Organization (to J.S.).
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Author notes
- Rebecca Piskorowski
Present address: Center for Neurobiology and Behavior, HHMI Columbia University, 1051 Riverside Drive, PI Annex, Room 633, New York, New York, 10032, USA - Ellen A. Lumpkin
Present address: Department of Neuroscience, Baylor College of Medicine, One Baylor Plaza, Room S636-A, Houston, Texas, 77030, USA
Authors and Affiliations
- Department of Cellular and Molecular Pharmacology, University of California–San Francisco, 600 16th Street, California, 94143-2140, San Francisco, USA
Jan Siemens & David Julius - Howard Hughes Medical Institute Mass Spectrometry Laboratory, University of California–Berkeley, California, 94720-3202, USA
Sharleen Zhou & David King - Department of Physiology, University of California–San Francisco, 600 16th Street, San Francisco, California, 94143-2280, USA
Rebecca Piskorowski & Ellen A. Lumpkin - Departments of Anatomy and Physiology and W. M. Keck Center for Integrative Neuroscience, University of California–San Francisco, 1550 4th Street, California, 94143-2722, San Francisco, USA
Tetsuro Nikai & Allan I. Basbaum
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Correspondence toDavid Julius.
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Supplementary information
Supplementary Notes
This file contains Supplementary Figures 1–7. Supplementary Figure 1 shows a representative chromatogram of vanillotoxin purification. Displayed are HPLC chromatograms and assessment of activity by ratiometric calcium imaging. Toxin purification is also described in detail. Supplementary Figures 2 and 3 describe the synthesis of VaTx1. Calcium imaging data display specific activation of the capsaicin receptor, TRPV1, by native and synthetic vanillotoxins. Supplementary Figures 4–6 extend the electrophysiological analysis of vanillotoxin effects on TRPV1 and on the voltage-gated potassium channel, Kv2.1 (see Figure 2 and 3 of the main manuscript). Supplementary Figure 7 displays the effects of crude Psalmopoeus cambridgei venom on trigeminal neurons cultured from wild-type or TRPV1-deficient mice, as assessed by ratiometric calcium imaging. (PDF 3060 kb)
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Siemens, J., Zhou, S., Piskorowski, R. et al. Spider toxins activate the capsaicin receptor to produce inflammatory pain.Nature 444, 208–212 (2006). https://doi.org/10.1038/nature05285
- Received: 26 July 2006
- Accepted: 27 September 2006
- Issue Date: 09 November 2006
- DOI: https://doi.org/10.1038/nature05285
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Editorial Summary
A taste for pain
Three peptides isolated from the venom of the West Indian tarantula Psalmopoeus cambridgei have been found to promote pain and inflammation by activating the same neuronal receptor as capsaicin, the hot component of chilli peppers. This suggests that tarantulas and chillis use similar tactics to deter predators. The newly discovered peptides are also unusual because they trigger an excitatory response. Peptides with similar structures that bind to other ion channels are already known, but are inhibitory.