Spider toxins activate the capsaicin receptor to produce inflammatory pain


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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: A subfamily of peptides from tarantula venom activates TRPV1.
Figure 2: Functional properties of purified vanillotoxins.
Figure 3: Analysis of vanillotoxin specificity.
Figure 4: VaTx3 activates capsaicin-sensitive trigeminal neurons and elicits TRPV1-dependent pain responses in mice.


  1. 1

    Schmidt, J. O. Biochemistry of insect venoms. Annu. Rev. Entomol. 27, 339–368 (1982)

    CAS  Article  Google Scholar 

  2. 2

    Chahl, L. A. & Kirk, E. J. Toxins which produce pain. Pain 1, 3–49 (1975)

    CAS  Article  Google Scholar 

  3. 3

    Escoubas, P. & Rash, L. Tarantulas: eight-legged pharmacists and combinatorial chemists. Toxicon 43, 555–574 (2004)

    CAS  Article  Google Scholar 

  4. 4

    Miller, C. The charybdotoxin family of K+ channel-blocking peptides. Neuron 15, 5–10 (1995)

    CAS  Article  Google Scholar 

  5. 5

    Terlau, H. & Olivera, B. M. Conus venoms: a rich source of novel ion channel-targeted peptides. Physiol. Rev. 84, 41–68 (2004)

    CAS  Article  Google Scholar 

  6. 6

    Caterina, M. J. et al. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389, 816–824 (1997)

    ADS  CAS  Article  Google Scholar 

  7. 7

    Swartz, K. J. & MacKinnon, R. An inhibitor of the Kv2.1 potassium channel isolated from the venom of a Chilean tarantula. Neuron 15, 941–949 (1995)

    CAS  Article  Google Scholar 

  8. 8

    Jordt, S. E., McKemy, D. D. & Julius, D. Lessons from peppers and peppermint: the molecular logic of thermosensation. Curr. Opin. Neurobiol. 13, 487–492 (2003)

    CAS  Article  Google Scholar 

  9. 9

    Voets, T., Talavera, K., Owsianik, G. & Nilius, B. Sensing with TRP channels. Nature Chem. Biol. 1, 85–92 (2005)

    CAS  Article  Google Scholar 

  10. 10

    Zhu, S., Darbon, H., Dyason, K., Verdonck, F. & Tytgat, J. Evolutionary origin of inhibitor cystine knot peptides. FASEB J. 17, 1765–1767 (2003)

    CAS  Article  Google Scholar 

  11. 11

    Swartz, K. J. & MacKinnon, R. Mapping the receptor site for hanatoxin, a gating modifier of voltage-dependent K+ channels. Neuron 18, 675–682 (1997)

    CAS  Article  Google Scholar 

  12. 12

    Oswald, R. E., Suchyna, T. M., McFeeters, R., Gottlieb, P. & Sachs, F. Solution structure of peptide toxins that block mechanosensitive ion channels. J. Biol. Chem. 277, 34443–34450 (2002)

    CAS  Article  Google Scholar 

  13. 13

    Takahashi, H. et al. Solution structure of hanatoxin1, a gating modifier of voltage-dependent K+ channels: common surface features of gating modifier toxins. J. Mol. Biol. 297, 771–780 (2000)

    CAS  Article  Google Scholar 

  14. 14

    Wang, J. M. et al. Molecular surface of tarantula toxins interacting with voltage sensors in Kv channels. J. Gen. Physiol. 123, 455–467 (2004)

    CAS  Article  Google Scholar 

  15. 15

    Escoubas, P., Diochot, S., Celerier, M. L., Nakajima, T. & Lazdunski, M. Novel tarantula toxins for subtypes of voltage-dependent potassium channels in the Kv2 and Kv4 subfamilies. Mol. Pharmacol. 62, 48–57 (2002)

    CAS  Article  Google Scholar 

  16. 16

    Zhang, P. F., Chen, P., Hu, W. J. & Liang, S. P. Huwentoxin-V, a novel insecticidal peptide toxin from the spider Selenocosmia huwena, and a natural mutant of the toxin: indicates the key amino acid residues related to the biological activity. Toxicon 42, 15–20 (2003)

    CAS  Article  Google Scholar 

  17. 17

    Voets, T. et al. The principle of temperature-dependent gating in cold- and heat-sensitive TRP channels. Nature 430, 748–754 (2004)

    ADS  CAS  Article  Google Scholar 

  18. 18

    Jung, J. et al. Capsaicin binds to the intracellular domain of the capsaicin-activated ion channel. J. Neurosci. 19, 529–538 (1999)

    CAS  Article  Google Scholar 

  19. 19

    Jordt, S. E. & Julius, D. Molecular basis for species-specific sensitivity to ‘hot’ chili peppers. Cell 108, 421–430 (2002)

    CAS  Article  Google Scholar 

  20. 20

    Gavva, N. R. et al. Molecular determinants of vanilloid sensitivity in TRPV1. J. Biol. Chem. 279, 20283–20295 (2004)

    CAS  Article  Google Scholar 

  21. 21

    Salinas, M. et al. The receptor site of the spider toxin PcTx1 on the proton-gated cation channel ASIC1a. J. Physiol. (Lond.) 570, 339–354 (2006)

    CAS  Article  Google Scholar 

  22. 22

    Lee, S. Y. & MacKinnon, R. A membrane-access mechanism of ion channel inhibition by voltage sensor toxins from spider venom. Nature 430, 232–235 (2004)

    ADS  CAS  Article  Google Scholar 

  23. 23

    Suchyna, T. M. et al. Bilayer-dependent inhibition of mechanosensitive channels by neuroactive peptide enantiomers. Nature 430, 235–240 (2004)

    ADS  CAS  Article  Google Scholar 

  24. 24

    Tominaga, M. et al. The cloned capsaicin receptor integrates multiple pain-producing stimuli. Neuron 21, 531–543 (1998)

    CAS  Article  Google Scholar 

  25. 25

    Ramu, Y., Xu, Y. & Lu, Z. Enzymatic activation of voltage-gated potassium channels. Nature 442, 696–699 (2006)

    ADS  CAS  Article  Google Scholar 

  26. 26

    Ramsey, I. S., Delling, M. & Clapham, D. E. An introduction to TRP channels. Annu. Rev. Physiol. 68, 619–647 (2006)

    CAS  Article  Google Scholar 

  27. 27

    Phillips, L. R. et al. Voltage-sensor activation with a tarantula toxin as cargo. Nature 436, 857–860 (2005)

    ADS  CAS  Article  Google Scholar 

  28. 28

    Jordt, S. E. et al. Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1. Nature 427, 260–265 (2004)

    ADS  CAS  Article  Google Scholar 

  29. 29

    Hamill, O. P., Marty, A., Neher, E., Sakmann, B. & Sigworth, F. J. Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pflügers Arch. 391, 85–100 (1981)

    CAS  Article  Google Scholar 

  30. 30

    Martinez-Caro, L. & Laird, J. M. Allodynia and hyperalgesia evoked by sciatic mononeuropathy in NKI receptor knockout mice. Neuroreport 11, 1213–1217 (2000)

    CAS  Article  Google Scholar 

Download references


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.).

Author information



Corresponding author

Correspondence to David Julius.

Ethics declarations

Competing interests

Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.

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)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Sign up for the Nature Briefing newsletter for a daily update on COVID-19 science.
Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing