A Single-Residue Switch for High Temperature Dependence of Thermal TRPV3 Channels

Abstract

Thermal TRP channels, a group of ion channels from the transient receptor potential family, play important functions in pain transduction and thermal sensation. The channels are directly activated by temperature, with strong temperature dependence. However, how temperature gates these channels remains poorly understood. One characteristic feature of some thermal TRP channels is hysteresis of gating. This is perhaps most prominent in vanilloid receptor TRPV3. The channel is initially only responsive to extreme heat with low activity, and only after repeated stimulation it becomes vigorously responsive to warm temperatures. Importantly, the hysteresis of activation is accompanied with a profound loss of the high temperature dependence of the channel, suggesting that the hysteresis involves structural changes in temperature sensing. Elucidation of such changes will therefore provide an opportunity to unravel the molecular mechanism underlying temperature sensing of thermal channels. Here we examine the molecular basis underlying hysteresis of heat activation of TRPV3. We show that the hysteresis is mediated by an N terminal domain proximal to membranes, the same region that we have previously identified for temperature sensing in heat sensitive vanilloid receptors. Upon exchange of the region, the heat activation of the channel becomes reversible and the temperature dependence becomes considerably reduced as the wild type channels after sensitization. Interesting much of the hysteresis effect can be attributed to a single residue near the TRP box. The position of the residue suggests a mechanism of temperature-dependent gating of thermal TRP channels involving an intracellular region assembled around the TRP domain.