# Human TRPV1 Channels are Functional Allosteric Receptors for Ciguatoxins and Brevetoxins

## TL;DR

This study shows that human TRPV1 channels can be activated by ciguatoxins and brevetoxins, especially under certain physiological conditions, which may explain some symptoms of ciguatera poisoning.

## Contribution

The study reveals that TRPV1 channels are functional allosteric receptors for ciguatoxins and brevetoxins, with effects modulated by physiological conditions.

## Key findings

- Ciguatoxins and brevetoxins modulate TRPV1 currents under low pH, oxidative stress, or presence of endogenous ligands.
- Brevetoxin 3 potentiates TRPV1 effects in the presence of anandamide.
- Ciguatoxins and brevetoxins act allosterically on TRPV1, increasing current intensity and shifting activation voltage.

## Abstract

Ciguatera poisoning (CP) is a foodborne illness caused
by the consumption of seafood containing ciguatoxins (CTXs). There
is a wide variety of symptoms associated with ciguatera poisoning;
however, the origin and physiological cause of many of them remains
still unclear. Although the primary effect of ciguatoxins and brevetoxins
(BTX) is their effect in voltage-gated sodium channels, in this work,
the effect of both toxins on human transient receptor potential vanilloid
1 (TRPV1) channels was investigated under different physiological
conditions that may contribute to CP. The results obtained showed
that different physiological conditions that may occur in the organism
potentiated the effect of ciguatoxins on TRPV1. Among these conditions,
low pH, the presence of oxidative stress products, or endogenous ligands
increased the TRPV1 currents induced by CTX3C and hyperpolarized their
activation voltage. In addition, neurotoxic shellfish poisoning symptomatology
(NSP), caused by brevetoxins, was previously linked to TRPV1 channels;
therefore, in this study brevetoxins and ciguatoxins were combined
to evaluate their effects on TRPV1 channels. The results obtained
demonstrated that brevetoxin 3 alone did not alter TRPV1 channel currents
or their activation; however, in the presence of the endogenous ligand
anandamide BTX3 effects were potentiated. Furthermore, an allosteric
effect of ciguatoxins and brevetoxins was observed, since the simultaneous
presence of 0.5 nM CTX3C with different concentrations of BTX activated
TRPV1 channels, increasing their maximum current intensity and hyperpolarizing
the activation voltage.