Animal Toxins Providing Insights into TRPV1 Activation Mechanism

Abstract

Beyond providing evolutionary advantages, venoms offer unique research tools, as they were developed to target functionally important proteins and pathways. As a key pain receptor in the nociceptive pathway, transient receptor potential vanilloid 1 (TRPV1) of the TRP superfamily has been shown to be a target for several toxins, as a way of producing pain to deter predators. Importantly, TRPV1 is involved in thermoregulation, inflammation, and acute nociception. As such, toxins provide tools to understand TRPV1 activation and modulation, a critical step in advancing pain research and the development of novel analgesics. Indeed, the phytotoxin capsaicin, which is the spicy chemical in chili peppers, was invaluable in the original cloning and characterization of TRPV1. The unique properties of each subsequently characterized toxin have continued to advance our understanding of functional, structural, and biophysical characteristics of TRPV1. By building on previous reviews, this work aims to provide a comprehensive summary of the advancements made in TRPV1 research in recent years by employing animal toxins, in particular DkTx, RhTx, BmP01, Echis coloratus toxins, APHCs and HCRG21. We examine each toxin’s functional aspects, behavioral effects, and structural features, all of which have contributed to our current knowledge of TRPV1. We additionally discuss the key features of TRPV1’s outer pore domain, which proves to be the target of the currently discussed toxins.

Centipede Venom Peptides Acting on Ion Channels

“…RhTx (τ-SLPTX 4 -Sm1a) 27 2/4 (C5-C16, C10-C23) TRPV1 activator, EC 50 = 521.5 nM. No effect on other TRPV channels [28,[49][50][51].…”

“…TRPV1 is a homotetrameric structure ( Figure 11). Each of the four subunits is composed of six transmembrane segments, S1-S6, with a pore-forming loop between S5 and S6 [51,89]. There are two major TRPV1 binding sites responsible for TRPV1's capacity to respond to a multitude of agonists, antagonists, and channel blockers.…”

“…There are two major TRPV1 binding sites responsible for TRPV1's capacity to respond to a multitude of agonists, antagonists, and channel blockers. One is the capsaicin binding site located in S3-S4, and the other is the outer pore region, which is essential for binding peptide toxins, such as DkTx [51] and RhTx [49]. antagonists, and channel blockers.…”

“…antagonists, and channel blockers. One is the capsaicin binding site located in S3-S4, and the other is the outer pore region, which is essential for binding peptide toxins, such as DkTx [51] and RhTx [49]. [49].…”

“…This peptide can produce excruciating pain by potently activating the nociceptor TRPV1. RhTx is a selective TRPV1 activator with an EC 50 of 521.5 nM and does not affect other TRPV channels [28,[49][50][51].…”