TRPA1 is an ion channel and has been proposed as a thermosensor across species. In invertebrate and ancestral vertebrates such as fly, mosquito, frog, lizard and snakes, TRPA1 serves as a heat receptor, a sensory input utilized for heat avoidance or infrared detection. However, in mammals, whether TRPA1 is a receptor for noxious cold is highly controversial, as channel activation by cold was observed by some groups but disputed by others. Here we attribute the discrepancy to species differences. We show that cold activates rat and mouse TRPA1 but not human or rhesus monkey TRPA1. At the molecular level, a single residue within the S5 transmembrane domain (G878 in rodent but V875 in primate) accounts for the observed difference in cold sensitivity. This residue difference also underlies the species-specific effects of menthol. Together, our findings identify the species-specific cold activation of TRPA1 and reveal a molecular determinant of cold-sensitive gating.

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Key pointsr Hypoxia is thought to depolarize glomus cells by inhibiting the outward K + current, which sets in motion a cascade of ionic events that lead to transmitter secretion, increased afferent carotid sinus nerve activity and increased ventilation.r Our study of Na + -permeable channels in glomus cells has revealed that hypoxia not only inhibits TASK background K + channels but also indirectly activates a non-selective cation channel with a single channel conductance of 20 pS. Under physiological conditions, the reversal potential of the cation channel is ß -28 mV, indicating that Na + influx is also involved in hypoxia-induced excitation of glomus cells.

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The goal of this study was to determine the molecular identity of a small conductance (~5-pS) background K+ channel expressed in trigeminal ganglion neurons. We tested the hypothesis that the 5-pS channel is a K2P channel by comparing the pharmacological and single-channel properties of THIK-1 expressed in HEK293 cells. As reported earlier, whole-cell THIK-1 current was inhibited by halothane and activated by arachidonic acid. Among 25 additional modulators tested, bupivacaine (100 μM), quinidine (50 μM) and Ba2+ (3 mM) and cold (10°C) were most effective inhibitors of THIK-1 current (>50% inhibition). In cell-attached patches with high KCl in the pipette and bath solutions, THIK-1 produced a small conductance (~5-pS) channel with a weak inwardly rectifying current-voltage relationship. Halothane, bupivacaine and cold inhibited the single-channel activities of both THIK-1 and the 5-pS channel in TG neurons, whereas arachidonic acid augmented them. THIK-1 expressed in HEK293 cells and the 5-pS channels in TG neurons were insensitive to hypoxia. Reverse transcriptase-PCR, western blot and immunocytochemical analyses suggested that THIK-1 mRNA and protein were expressed in TG neurons. These results show that THIK-1 is functionally expressed in TG neurons and contributes to the background K+ conductance.