# Ligand-induced cold activation of TRPV3

## TL;DR

This study shows that TRPV3 channels can be activated by cold temperatures when bound to a specific compound, revealing two distinct temperature-dependent activation pathways.

## Contribution

The paper demonstrates cold activation of TRPV3 channels through ligand-induced changes, revealing dual temperature-dependent gating pathways.

## Key findings

- Oxidized TRPV3 can be activated and inactivated below 30°C through cold activation.
- THCV binding prevents inactivation above 30°C by releasing lipid at the active site.
- Two distinct temperature-dependent pathways for TRPV3 gating were identified.

## Abstract

Both hot and cold sensation of the homotetrameric thermosensitive transient receptor potential vanilloid 1–4 (TRPV1–4) channels have been predicted by a single Gibbs-Helmholtz equation for a change in molar heat capacity. However, cold activation has not been confirmed for those heat-responsive TRPV1–4 channels. Given the cooperative heat unfolding and non-cooperative cold unfolding behaviors in proteins, two different open states at low and high temperatures should be detected in TRPV1–4 channels. To test this hypothesis, the temperature-dependent quaternary and tertiary structures of oxidized TRPV3 in the presence and absence of the natural cannabinoid tetrahydrocannabivarin (THCV) were characterized along a lipid-dependent minimal gating pathway. Further thermoring analyses showed that gating state-dependent thermostability allowed oxidized TRPV3 to be activated and then inactivated only below 30°C. However, no inactivation would be observed above 30°C once the lipid at the active vanilloid site was released by THCV binding. Therefore, such two temperature-dependent gating pathways of oxidized TRPV3 actually resulted from cold and heat activation. (161 words)