Human and Mouse TRPA1 Are Heat and Cold Sensors Differentially Tuned by Voltage.

Viktor Sinica,Lucie Zimova,Kristyna Barvikova,Lucie Macikova,Ivan Barvik,Viktorie Vlachova

doi:10.3390/cells9010057

Viktor Sinica, Lucie Zimova + Show 4 more

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https://doi.org/10.3390/cells9010057

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Abstract

Transient receptor potential ankyrin 1 channel (TRPA1) serves as a key sensor for reactive electrophilic compounds across all species. Its sensitivity to temperature, however, differs among species, a variability that has been attributed to an evolutionary divergence. Mouse TRPA1 was implicated in noxious cold detection but was later also identified as one of the prime noxious heat sensors. Moreover, human TRPA1, originally considered to be temperature-insensitive, turned out to act as an intrinsic bidirectional thermosensor that is capable of sensing both cold and heat. Using electrophysiology and modeling, we compare the properties of human and mouse TRPA1, and we demonstrate that both orthologues are activated by heat, and their kinetically distinct components of voltage-dependent gating are differentially modulated by heat and cold. Furthermore, we show that both orthologues can be strongly activated by cold after the concurrent application of voltage and heat. We propose an allosteric mechanism that could account for the variability in TRPA1 temperature responsiveness.

Highlights

The transient receptor potential (TRP) channel subtype A1 (TRPA1) is a polymodal sensor that is implicated in thermal and chemical nociception
Previous studies have shown that the cold sensitivity of mouse TRPA1 (mTRPA1) can be described by a two-state model in which temperature directly affects the equilibrium between the open and closed states of the channel, based on global changes in enthalpy and entropy during channel gating [17]
To compare the voltage-dependence and relaxation kinetics between human TRPA1 (hTRPA1) and mTRPA1, we measured whole-cell currents in response to a voltage step protocol akin to that used previously by [17], consisting of 400-ms steps ranging from −150 to +100 mV, followed by a 400-ms step to −150 mV (Figure 1A–D)

Summary

Introduction

The transient receptor potential (TRP) channel subtype A1 (TRPA1) is a polymodal sensor that is implicated in thermal and chemical nociception. Across different species, this channel serves as a key receptor for electrophilic irritant compounds, evoking defensive responses [1,2,3]. The temperature sensitivity of TRPA1, on the other hand, has been reported to be a less evolutionarily conserved activation mode or alternatively occurring at the expense of chemical sensitivity [2,4]. The physiological role of this channel as a heat sensor has likely changed during evolution, potentially altering the preferred temperature ranges among species [5,6] or enabling some of them to detect and transduce infrared signals [4]. TRPA1 has long been considered to function as a cold receptor [13,14,15,16,17,18]

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