TRPM2 and warmth sensation

The abilities to detect warmth and heat are critical for the survival of all animals, both in order to be able to identify suitable thermal environments for the many different activities essential for life and to avoid damage caused by extremes of temperature. Several ion channels belonging to the TRP family are activated by non-noxious warmth or by heat and are therefore plausible candidates for thermal detectors, but identifying those that actually regulate warmth and heat detection in intact animals has proven problematic. TRPM2 has recently emerged as a likely candidate for the detector of non-noxious warmth, as it is expressed in sensory neurons, and mice show deficits in the detection of warmth when TRPM2 is genetically deleted. TRPM2 is a chanzyme, containing a thermally activated TRP ion channel domain attached to a C-terminal motif, derived from a mitochondrial ADP ribose pyrophosphatase, that confers on the channel sensitivity to ADP ribose and reactive oxygen species such as hydrogen peroxide. Several open questions remain. Male mammals prefer cooler environments than female, but the molecular basis of this sex difference is unknown. TRPM2 plays a role in regulating body temperature, but are other warmth-detecting mechanisms also involved? TRPM2 is expressed in autonomic neurons, but does it confer a sensory function in addition to the well-known motor functions of autonomic neurons? TRPM2 is thought to play important roles in the immune system, in pain and in insulin secretion, but the mechanisms are unclear. TRPM2 has to date received less attention than many other members of the TRP family but is rapidly assuming importance both in normal physiology and as a key target in disease pathology.