Editors' ChoicePharmacology

Why Spider Bites Hurt

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Science's STKE  14 Nov 2006:
Vol. 2006, Issue 361, pp. tw386
DOI: 10.1126/stke.3612006tw386

Peptide toxins produced by venomous creatures contain potent inhibitors of channel activity, and these inhibitors contribute to the shock, paralysis, and death that can accompany bites from one of these organisms. Siemens et al. show that, in addition to these potent channel inhibitors, spider venom has peptides of the inhibitor cysteine knot (ICK) family that activate transient receptor potential (TRPs) channels associated with pain perception. Venom from 22 spiders and scorpions was applied to human embryonic kidney (HEK) 293 cells transfected with TRPV1, TRPA1, or TRPM8 (all TRP channels found in primary afferent neurons, the activation of which is associated with pain and inflammation). Venom from one species of tarantula stimulated an increase in calcium signaling when applied to the TRPV1-expressing cells but not the TRPA1- or TRPM8-expressing cells. The active peptides were isolated and sequenced and named vanillotoxins 1, 2, and 3 (VaTx1, VaTx2, and VaTx3). VaTx1 and VaTx2 were most similar to an ICK that inhibits Kv2-type voltage-gated potassium channels, whereas VaTx3 resembles a toxin (huwentoxin 5) from another spider that has no known target. Huwentoxin 5 also triggered a calcium signal in TRPV1-expressing cells. VaTx1 and VaTx2 inhibited Kv2.1 activity, although VaTx2 was more potent at activating the TRPV1 channel than at inhibiting the Kv2.1 channel. VaTx3 did not inhibit Kv2.1 channels. Dose-response analysis showed that VaTx3 was most potent, followed by VaTx2, then VaTx1, and the abundance of these toxins in the venom was inversely correlated with their potency. To confirm the relevance of these results in pain transmission, the authors demonstrated that dissociated sensory neurons from mouse trigeminal ganglia responded to VaTx2 or VaTx3 with a robust calcium signal and that this response was abolished in neurons from mice deficient in TRPV1. Injection of VaTx3 into the paws of mice caused pain-related behaviors and swelling; these responses were absent in the TRPV1-deficient mice. These results provide mechanistic insight into the pain associated with bites from venomous animals and also new tools for studying TRP channel function.

J. Siemens, S. Zhou, R. Piskorowski, T. Nikai, E. A. Lumpkin, A. I. Basbaum, D. King, D. Julius, Spider toxins activate the capsaicin receptor to produce inflammatory pain. Nature 444, 208-212 (2006). [PubMed]

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