Thermodynamic coupling between cold and heat activations of TRPV2

The homotetrameric thermosensitive transient receptor potential vanilloid 2 (TRPV2) channel is a biological macromolecule with unique high temperature threshold and sensitivity. However, the underlying thermodynamic basis has not been well understood. In this computational study, the 3D cryo-EM structures of rat TRPV2 in response to various chemical perturbations at different sites at low temperatures were quantified at the tertiary and quaternary levels using a highly sensitive thermoring model. The results indicated that a putative stable pre-open closed state without a lipid at the well-known active vanilloid site exhibited at least three weakest tertiary noncovalent bridges on the protein surface as primary thermal sensors with matched thresholds for initial heat activation. Any chemical perturbation away from these sensors activated the channel but with lower cold sensitivity. In contrast, when the sensors were simultaneously exposed to a mild detergent, together with hydrolysis of nearby charged residues at the membrane surface, the channel could be opened with the unique high cold sensitivity similarly to mirror the initial heat sensation. Further, disrupting intersubunit interactions near the heat sensors was required for full channel opening at both upper and lower gates. Therefore, the heat capacity mechanism, once cross-examined, could be applied to elucidate the unique thermoring basis for the sharp heat response of thermosensitive TRPV2 above body temperature. (213 words)