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Sci Adv. 2017 Aug 2;3(8):e1700810. doi: 10.1126/sciadv.1700810. eCollection 2017 Aug.

A bimodal activation mechanism underlies scorpion toxin-induced pain.

Author information

1
Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan 650223, China.
2
Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
3
Department of Physiology and Membrane Biology, University of California, Davis, Davis, CA 95616, USA.
4
School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.

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.

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