PT  - JOURNAL ARTICLE
AU  - Yang, Shilong
AU  - Yang, Fan
AU  - Zhang, Bei
AU  - Lee, Bo Hyun
AU  - Li, Bowen
AU  - Luo, Lei
AU  - Zheng, Jie
AU  - Lai, Ren
TI  - A bimodal activation mechanism underlies scorpion toxin–induced pain
AID  - 10.1126/sciadv.1700810
DP  - 2017 Aug 01
TA  - Science Advances
PG  - e1700810
VI  - 3
IP  - 8
4099  - http://advances.sciencemag.org/content/3/8/e1700810.short
4100  - http://advances.sciencemag.org/content/3/8/e1700810.full
SO  - Sci Adv2017 Aug 01; 3
AB  - 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.