The TRPM2 ion channel is required for sensitivity to warmth

Thermally activated ion channels are known to detect the entire thermal range from extreme heat (TRPV2), painful heat (TRPV1, TRPM3 and ANO1), non-painful warmth (TRPV3 and TRPV4) and non-painful coolness (TRPM8) through to painful cold (TRPA1) 1 , 2 , 3 , 4 , 5 , 6 , 7 . Genetic deletion of each of these ion channels, however, has only modest effects on thermal behaviour in mice 6 , 7 , 8 , 9 , 10 , 11 , 12 , with the exception of TRPM8, the deletion of which has marked effects on the perception of moderate coolness in the range 10–25 °C 13 . The molecular mechanism responsible for detecting non-painful warmth, in particular, is unresolved. Here we used calcium imaging to identify a population of thermally sensitive somatosensory neurons which do not express any of the known thermally activated TRP channels. We then used a combination of calcium imaging, electrophysiology and RNA sequencing to show that the ion channel generating heat sensitivity in these neurons is TRPM2. Autonomic neurons, usually thought of as exclusively motor, also express TRPM2 and respond directly to heat. Mice in which TRPM2 had been genetically deleted showed a striking deficit in their sensation of non-noxious warm temperatures, consistent with the idea that TRPM2 initiates a ‘warm’ signal which drives cool-seeking behaviour. The neuronal mechanism for the detection of non-painful warm stimuli has remained unclear; mammalian TRPM2 ion channel is shown to be required for warmth detection in the non-noxious range of 33–38 °C, and surprisingly to mediate responses to warmth in the autonomic nervous system. An ion channel responding to 'comfortable' warmth Despite the identification of several members of the TRP family of ion channels as heat-sensitive, the neuronal mechanism for the detection of non-painful warm stimuli has remained unclear, because genetic deletion of obvious candidates, such as TRPV3 and TRPV4, has had no effect on thermosensation. Rather than working with cloned channels, as is commonly done, Chun-Hsiang Tan and Peter McNaughton studied the responses of actual sensory neurons to thermal stimuli, then used an RNA-sequencing strategy to identify TRPM2 as genetically required for warmth detection in the non-noxious range of 33–38 °C, and, surprisingly, to mediate warm sensations in the autonomic nervous system.