Temperature-dependent gating pathways in TRPV3

Both hot and cold sensations 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, the heat capacity model has not been examined for TRPV3 channels involving inactivation. Given the mirrored heat and cold sensitivity in TRPV1 with a shared starter, the same case should be detected for TRPV3. 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) at the active vanilloid site were characterized along a lipid-dependent gating pathway. Further thermoring analyses showed that gating state-dependent thermostability allowed oxidized TRPV3 to be activated and then inactivated by THCV 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. More importantly, despite the distinct tertiary and quaternary structures in cold- and heat-evoked open states, the initial cold activation of oxidized TRPV3 still shared a similar thermosensitivity with heat activation. Therefore, such two temperature-dependent gating pathways of oxidized TRPV3 actually still resulted from symmetric cold and heat activation, supporting the heat capacity model, regardless of the subsequent inactivation. In contrast, the initial inactivation resulted in unpredictable pore dilation along with a tetramer-to-pentamer transition.