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.

Department of Cellular Neurophysiology Institute of Physiology of the Czech Academy of Sciences 142 20 Prague Czech Republic

Department of Cellular Neurophysiology Institute of Physiology of the Czech Academy of Sciences 142 20 Prague Czech Republic Department of Physical and Macromolecular Chemistry Faculty of Science Charles University 128 00 Prague Czech Republic

Division of Biomolecular Physics Institute of Physics Faculty of Mathematics and Physics Charles University 121 16 Prague Czech Republic

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