Seminar Detail

The discovery of the TRP family of ion channels was a significant advance in our understanding of thermosensation.  However, genetic deletion of TRPV1, TRPV2, TRPV3, TRPV4, TRPM8, TRPM3, and TRPA1, however, has only modest effects on physiological thermal behavior in mice, with the exception of TRPM8, the deletion of which has marked effects on the perception of moderate coolness.  In addition, these knockout mice thermoregulate normally.  Although TRPV3 and TRPV4 were initially suggested to participate in the detection of non-painful warmth, later findings showing that mice deficient in both TRPV3 and TRPV4 show thermal preference behavior similar to wild type mice on a thermal gradient and little or no change in acute heat perception indicate that the molecular mechanism responsible for detecting non-painful warmth remains elusive.  Recently, we showed that TRPM2 ion channel is required for warmth sensation.  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, including TRPV1, TRPV2, TRPV3, TRPV4, and TRPM3.  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.  Most importantly, 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 behavior.  These results demonstrate that the molecular mechanism underlying warmth sensation is mediated by TRPM2.