ThermoTRP channels and beyond: mechanisms of temperature sensation

The identification of a family of transient receptor potential (TRP) ion channels that are gated by specific temperatures has been an important advance in the elucidation of the molecular mechanisms of thermosensitivity.Hot temperatures in the noxious range (≥ 42°C) activate the channels Trpv1 and Trpv2. Trpv1 is also activated by low pH and by capsaicin, whereas Trpv2, which has a higher activation threshold, is not.Warm temperatures in the innocuous range (34–42°C) activate the channels Trpv3 and Trpv4. Although the activation properties of these channels parallel the behaviour of the relevant afferent sensory fibres, there is no evidence yet for a functional role of Trpv3 and Trpv4 in vivo.Cool and cold temperatures activate the channels Trpv8 and Anktn1. Trpm8 is also activated by menthol, whereas the activation threshold of Anktm1 is set at temperatures that humans tend to regard as painfully cold.According to the labelled-line hypothesis, distinct sets of sensory neurons are tuned to convey specific sensory information through dedicated pathways to the central nervous system. However, the exact connectivity between the primary thermoreceptors and their spinal interneuron targets is not clear. It will be important to establish whether the pattern of expression of the different thermoTRPs sheds light on the organization of those dedicated pathways.Another enigma concerns the gating mechanism of thermoTRPs by hot or cold temperatures. Although their interaction with cytoplasmic elements has been proposed to be important, the evidence is still incomplete.In addition to thermoTRPs, other mechanisms for thermosensation have been put forward, They include the inhibition of background potassium conductances (perhaps the TREK-1 channel) or of a Na+/K+ ATPase, or the activation of pH-sensitive channels such as ASIC and DRASIC.In invertebrates, the neuroanatomy of thermosensation is partially understood, but the molecular mechanisms remain to be elucidated. Recent evidence indicates that TRP channels might also be involved in these organisms.An important development in this field will be the generation of mice that lack the different thermoTRPs, as they will make it possible to establish their function in vivo.