title: Spider toxins activate the capsaicin receptor to produce inflammatory pain.
abstract: Bites and stings from venomous creatures can produce pain and inflammation as part of their defensive strategy to ward off predators or competitors. 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. 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 pathway. In contrast with the predominant role of ICK toxins as channel inhibitors, 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.
authors.affiliation: Department of Cellular and Molecular Pharmacology, University of California-San Francisco, 600 16th Street, San Francisco, California 94143-2140, USA.
authors.forename: Jan
authors.initials: J
authors.lastname: Siemens
authors.forename: Sharleen
authors.initials: S
authors.lastname: Zhou
authors.forename: Rebecca
authors.initials: R
authors.lastname: Piskorowski
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Nikai
authors.forename: Ellen A
authors.initials: EA
authors.lastname: Lumpkin
authors.forename: Allan I
authors.initials: AI
authors.lastname: Basbaum
authors.forename: David
authors.initials: D
authors.lastname: King
authors.forename: David
authors.initials: D
authors.lastname: Julius
mesh_terms: D000818:Animals; D002460:Cell Line; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D015640:Ion Channel Gating / Q000187:drug effects*; D051379:Mice; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism; D010146:Pain / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D018408:Patch-Clamp Techniques; D051381:Rats; D013111:Spider Venoms / Q000737:chemistry / Q000494:pharmacology*; D013112:Spiders / Q000737:chemistry* / Q000502:physiology; D013379:Substrate Specificity; D050916:TRPV Cation Channels / Q000819:agonists* / Q000378:metabolism*
chemical_list: D013111:Spider Venoms; D050916:TRPV Cation Channels