A Specialized Pore Turret in the Mammalian Cation Channel TRPV1 Is Responsible for Distinct and Species-Specific Heat Activation Thresholds

The transient receptor potential vanilloid 1 (TRPV1) is a heat-activated cation channel that plays a crucial role in ambient temperature detection and thermal homeostasis. Although several structural features of TRPV1 have been shown to be involved in the heat-induced activation of the gating process, the physiological significance of only a few of these key elements has been evaluated in an evolutionary context. Here, using transient expression in HEK293 cells, electrophysiological recordings, and molecular modeling, we show that the pore turret contains both structural and functional determinants that set the heat activation thresholds of distinct TRPV1 orthologs in mammals whose body temperatures widely fluctuate. We found that TRPV1 from the bat Carollia brevicauda (fbTRPV1) exhibits a lower threshold temperature of channel activation than its human ortholog and that three bat-specific amino acid substitutions located at the pore turret are sufficient to determine this threshold temperature. Furthermore, the structure of the TRPV1 pore turret appears to be of physiological and evolutionary significance for differentiating the heat-activated threshold among species-specific TRPV1 orthologs. These findings support a role of the TRPV1 pore turret in tuning the heat-activated threshold and suggest that its evolution was driven by adaption to specific physiological traits within mammals exposed to variable temperatures.