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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.

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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.
Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
Department of Physiology and Membrane Biology, University of California, Davis, Davis, CA 95616, USA.
School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.


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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