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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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.).
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.