Abstract
TRPA1 was first identified as a noxious cold receptor in mice in 2003. Multiple TRPA1 genes have since been isolated, indicating that TRPA1 emerged early in evolution and showing the existence of TRPA1 variants in a range of species, including insects. Although TRPA1 channels in insects to birds (endotherms) show heat-dependent activation that indicates the importance of TRPA1 for detecting ambient warm to hot temperatures, in mammals TRPA1 temperature sensitivity remains controversial. Analyses of insect TRPA1 highlighted several important structural motifs, but the structural basis of heat-evoked activation is still unclear. Furthermore, atomic-level structures of TRPA1 solved using single particle analysis with cryo-electron microscopy did not reveal a basis for TRPA1 thermosensitivity. Recent studies did demonstrate that human TRPA1 has bimodal thermosensitivity and mouse TRPA1 is involved in noxious heat sensitivity, but additional systematic analyses are needed to determine the general mechanism of mammalian TRPA1 thermosensitivity.