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A bimodal activation mechanism underlies scorpion toxin-induced pain.

ABSTRACT: Venomous animals use peptide toxins for hunting and self-defense. To achieve these goals, toxins need to bind to their targets with high affinity due to the small amount that a single bite or sting can deliver. The scorpion toxin BmP01 is linked to sting-induced excruciating pain; however, the reported minimum concentrations for activating TRPV1 channel or inhibiting voltage-gated potassium (Kv) channels (both in the micromolar range) appear too high to be biologically relevant. We show that the effective concentration of BmP01 is highly pH-dependent-it increases by about 10-fold in inhibiting Kv channels upon a 1-U drop in pH but decreases more than 100-fold in activating TRPV1. Mechanistic investigation revealed that BmP01 binds to one of the two proton-binding sites on TRPV1 and, together with a proton, uses a one-two punch approach to strongly activate the nociceptive channel. Because most animal venoms are acidic, proton-facilitated synergistic action may represent a general strategy for maximizing toxin potency.

SUBMITTER: Yang S

PROVIDER: S-EPMC5540258 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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A bimodal activation mechanism underlies scorpion toxin-induced pain.

Yang Shilong S Yang Fan F Zhang Bei B Lee Bo Hyun BH Li Bowen B Luo Lei L Zheng Jie J Lai Ren R

Science advances 20170802 8

Venomous animals use peptide toxins for hunting and self-defense. To achieve these goals, toxins need to bind to their targets with high affinity due to the small amount that a single bite or sting can deliver. The scorpion toxin BmP01 is linked to sting-induced excruciating pain; however, the reported minimum concentrations for activating TRPV1 channel or inhibiting voltage-gated potassium (Kv) channels (both in the micromolar range) appear too high to be biologically relevant. We show that the ...[more]

PMID: 28782041

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Project description:Among scorpion species, the Buthidae produce the most deadly and painful venoms. However, little is known regarding the venom components that cause pain and their mechanism of action. Using a paw-licking assay (Mus musculus), this study compared the pain-inducing capabilities of venoms from two species of New World scorpion (Centruroides vittatus, C. exilicauda) belonging to the neurotoxin-producing family Buthidae with one species of non-neurotoxin producing scorpion (Vaejovis spinigerus) in the family Vaejovidae. A pain-inducing ?-toxin (CvIV4) was isolated from the venom of C. vittatus and tested on five Na(+) channel isoforms.C. vittatus and C. exilicauda venoms produced significantly more paw licking in Mus than V. spinigerus venom. CvIV4 produced paw licking in Mus equivalent to the effects of whole venom. CvIV4 slowed the fast inactivation of Na(v)1.7, a Na(+) channel expressed in peripheral pain-pathway neurons (nociceptors), but did not affect the Na(v)1.8-based sodium currents of these neurons. CvIV4 also slowed the fast inactivation of Na(v)1.2, Na(v)1.3 and Na(v)1.4. The effects of CvIV4 are similar to Old World ?-toxins that target Na(v)1.7 (AahII, BmK MI, LqhIII, OD1), however the primary structure of CvIV4 is not similar to these toxins. Mutant Na(v)1.7 channels (D1586A and E1589Q, DIV S3-S4 linker) reduced but did not abolish the effects of CvIV4.This study: 1) agrees with anecdotal evidence suggesting that buthid venom is significantly more painful than non-neurotoxic venom; 2) demonstrates that New World buthids inflict painful stings via toxins that modulate Na(+) channels expressed in nociceptors; 3) reveals that Old and New World buthids employ similar mechanisms to produce pain. Old and New World ?-toxins that target Na(v)1.7 have diverged in sequence, but the activity of these toxins is similar. Pain-inducing toxins may have evolved in a common ancestor. Alternatively, these toxins may be the product of convergent evolution.

Dataset Information

A bimodal activation mechanism underlies scorpion toxin-induced pain.

Publications

A bimodal activation mechanism underlies scorpion toxin-induced pain.

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