1. Department of Cellular and Molecular Pharmacology, University of California–San Francisco, 600 16th Street, San Francisco, California 94143-2140, USA
2. Howard Hughes Medical Institute Mass Spectrometry Laboratory, University of California–Berkeley, California 94720-3202, USA
3. Department of Physiology, University of California–San Francisco, 600 16th Street, San Francisco, California 94143-2280, USA
4. Departments of Anatomy and Physiology and W. M. Keck Center for Integrative Neuroscience, University of California–San Francisco, 1550 4th Street, San Francisco, California 94143-2722, USA
5. Present addresses: Center for Neurobiology and Behavior, HHMI Columbia University, 1051 Riverside Drive, PI Annex, Room 633 New York, New York 10032, USA (R.P.); Department of Neuroscience, Baylor College of Medicine, One Baylor Plaza, Room S636-A, Houston, Texas 77030, USA (E.A.L.).

Correspondence to: David Julius¹ Correspondence and requests for materials should be addressed to D.J. (Email: julius@cmp.ucsf.edu).

Abstract

Bites and stings from venomous creatures can produce pain and inflammation as part of their defensive strategy to ward off predators or competitors^{1, 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 death^{3, 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 inhibitors^{5, 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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