Ligand-induced cold activation of TRPV3

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).