Abstract
The capsaicin receptor TRPV1 ion channel is a polymodal nociceptor that responds to heat with exquisite sensitivity through an unknown mechanism. Here we 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.
Highlights
The capsaicin receptor TRPV1 ion channel is a polymodal nociceptor that responds to heat with exquisite sensitivity through an unknown mechanism
While TRPV1 was initially cloned as a receptor for capsaicin, the pungent compound in hot chili peppers, it is known as a prototypical heat-sensing channel involved in detecting ambient environment to maintain stable body temperature in mammals and transduce heat pain[13,15]
The pain behaviour was distinct from those mediated by inflammation but exhibited a close resemblance to that associated with capsaicin injection
Summary
The capsaicin receptor TRPV1 ion channel is a polymodal nociceptor that responds to heat with exquisite sensitivity through an unknown mechanism. We 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. 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, providing crucial new structural information on the heat activation machinery. Many of the 3,000 centipede species are highly venomous[6,7]; their bites are known to kill small animals such as rodent, snake and even human[8,9]. We used a combination of animal behaviour tests, nuclear magnetic resonance (NMR), mutagenesis, electrophysiology, fluorescence imaging and Rosetta-based structural modelling to elucidate the structural and molecular basis enabling RhTx to interact with and activate TRPV1 to produce sharp pain
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