A specialized pore turret in the mammalian cation channel TRPV1 is responsible for distinct and species-specific heat activation thresholds

Longhui Chai,Simon Vu,Shilong Yang,Jie Zheng,Guangxu Du,Zhihao Yao,KeWei Wang,Yuhua Tian

doi:10.1074/jbc.ra120.013037

Abstract

The transient receptor potential vanilloid 1 (TRPV1) channel 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 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 fluctuate widely. We found that TRPV1 from the bat Carollia brevicauda exhibits a lower threshold temperature of channel activation than does its human ortholog and three bat-specific amino acid substitutions located in 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 for the TRPV1 pore turret in tuning the heat-activated threshold, and they suggest that its evolution was driven by adaption to specific physiological traits among mammals exposed to variable temperatures.

Highlights

Accurate detection and response to ambient temperature are of paramount importance for the survival of all organisms living in environments with fluctuating ambient temperatures [1]
These results suggest that fruit bat TRPV1 (fbV1) shares similar physical and chemical sensitivities with other mammalian transient receptor potential vanilloid 1 (TRPV1) channels
Recent studies have suggested that conformational changes of the turret-containing TRPV1 pore domain are required for heat activation [11, 38,39,40] or even are sufficient to be functionally transplanted with heat activation properties into a temperature-insensitive ion channel [31]

Summary

Introduction

Accurate detection and response to ambient temperature are of paramount importance for the survival of all organisms living in environments with fluctuating ambient temperatures [1]. We found that all of the chimeric channels exhibited high sensitivity to capsaicin (Table 1 and Fig. S1) and heat (Fig. 3B, Table 1, and Fig. S2) without disruption of the channel function, which allowed us to test the role of the pore regions of fbV1 and hV1 in tuning the threshold temperature.

Results

Conclusion