We need to be able to make quick judgements about warmth and cold in the external environment, in order to choose a comfortable ambient temperature and to avoid dangerous extremes of heat. When the TRP ion channel family was cloned it seemed that this problem was solved, because a spectrum of thermally activated TRP channels responded to temperatures from extreme cold to painful heat. However, as knockout mice for each of these thermo-TRP channels have been constructed, it has become apparent that many of the supposed thermal detectors actually have little influence on thermal behaviour at the level of the whole organism. In particular, genetic deletion of potential warm-sensitive ion channels TRPV3 and TRPV4 had no effect on behavioural warmth sensation.
With this background we set out to establish the molecular mechanism responsible for warmth sensation. We used calcium imaging to monitor the responses of isolated somatosensory neurons to warm and hot stimuli. We eliminated neurons responding to agonists for known heat-sensitive TRP channels and focussed on a population of neurons that expressed a novel thermal response. We used an RNA sequencing strategy to identify the thermally-sensitive ion channel expressed in these neurons as TRPM2, a TRP channel not previously suspected to be involved in warmth sensation.
The story came together in an interesting way when we looked at thermal sensation in mice in which TRPM2 had been genetically deleted. Wild-type mice are most comfortable at an ambient temperature of 33 degrees Centigrade, and they avoid warmer temperatures such as 38 degrees. The TRPM2 knockout mice, however, were unable to distinguish between 33 degrees and 38 degrees, suggesting that removal of TRPM2 had ablated a “warm” detector. Both mice, however, avoided hot temperatures such as 43 degrees, at which TRPV1 and TRPM3, the known “painful heat” detectors, are activated. This work identifies TRPM2 as a novel thermal detector which is responsible for the detection of non-painful warmth.