Understanding the mechanism of pain receptor activation by centipede toxin

Understanding the mechanism of pain receptor activation by centipede toxin
Venomous animals use toxins to paralyse prey for hunting or to inflict pain during self-defence.

A large fraction of the known nerve toxins from spider, snake, scorpion, sea anemone and cone snail (the 5S’s) achieve these purposes by targeting ion channels. Binding of animal toxins either blocks ion permeation or interferes with activation gating, therefore disrupting the normal function of their targets.

For example, snake α-bungarotoxin inhibits nicotinic acetylcholine receptor of neuromuscular junction, causing respiratory paralysis and death. Scorpion charybdotoxin and spider hanatoxin inhibit voltage-gated Kv channels, causing hyper-excitability of the nervous system.

The action of most known animal toxins is inhibitory in nature. Noticeably, spider toxins VaTx4 and DkTx5 are found to activate nociceptor TRPV1 ion channel, hence representing a unique defence mechanism.

The capsaicin receptor TRPV1 ion channel is a polymodal nociceptor that responds to heat with exquisite sensitivity through an unknown mechanism.
Scientists report the identification of a novel toxin, RhTx, from the venom of the Chinese red-headed centipede that potently activates TRPV1 to produce excruciating pain.

RhTx is a 27-amino-acid small peptide that forms a compact polarized molecule with very rapid binding kinetics and high affinity for TRPV1. We show that RhTx targets the channel’s heat activation machinery to cause powerful heat activation at body temperature.

The RhTx–TRPV1 interaction is mediated by the toxin’s highly charged C terminus, which associates tightly to the charge-rich outer pore region of the channel where it can directly interact with the pore helix and turret.

These findings demonstrate that RhTx binding to the outer pore can induce TRPV1 heat activation, therefore providing crucial new structural information on the heat activation machinery.