The study by McKemy et al is of great significance, as it led to the identification and characterization of the first cold receptor. This study also suggests that TRP channels have a general role in thermosensation, as all the previously identified TRP channels are sensitive to heat.
Dhaka et al (2007) show that TRPM8 is required for sensitivity to innocuous cool stimuli and is also involved in sensing noxious cold temperatures. The TRPM8 knockout mice generated in this study have only a partial deficit in sensing noxious cold stimuli, so it is most likely that at least one other cold receptor is involved. Story et al (2003) identified a second cold receptor, TRPA1/ ANKTM1, but its role under physiological conditions is still in question.
There are likely to be other, as yet unidentified, cold sensitive TRP channels. Thermosensation may involve a combinatorial code of thermoTRPs, such that a given repertoire of receptors, each activated by a specified temperature range, confers upon primary sensory afferents sensitivity to cold stimuli of different intensities.
This study also shows that TRPM8 mediates cooling-induced analgesia. TRPM8 is known to be upregulated in subsets of DRG cells following nerve injury leading to hypersensitivity and allodynia (Proudfoot et al, 2006); the channel could therefore be a useful target for novel analgesics.
Takashima et al (2007) show that TRPM8+ primary sensory neurons are neurochemically and anatomically heterogeneous. TRPM8+ sensory neurons express markers of A-delta fibres and C-fibres, and of presumptive nociceptors and non-nociceptors. A significant proportion of TRPM8+ neurons (~60%) express no other markers; thus TRPM8 may be a marker which distinguishes cold fibres from other primary sensory neurons.
This study also shows that different types of TRPM8+ sensory neurons have distinct receptive fields in the periphery, and therefore provides a neuroanatomical basis for the multiple role of TRPM8 in cold thermosensation. It also raises the possibility that TRPM8 is expressed in two labeled lines of cold fibres, one consisting of nociceptors, the other of non-nociceptors.
The three studies discussed here contribute significantly to our understanding of cold thermosensation. Together, they link events at the molecular level with behavioural responses, and provide an anatomical basis for the multiple roles of TRPM8. However, the primary sensory neurons which express TRPM8+ are not yet characterized properly, and other key questions remain unanswered. For example, how do TRP channels sense changes in skin temperature, and exactly how do these temperature changes activate a TRP channel?
Bautista, D. M., Siemens, J., Glazer, J. M., Tsuruda, P. R., Basbaum, A. I., Stucky, C. L., Jordt, S.-V. & Julius, D. (2007). The menthol receptor TRMP8 is the principal detector of environmental cold. Nature 448: 204-209.
Colburn, R. W., Lubin, M. L., Stone Jr., D. J., Wang, Y., Lawrence, D., D’Andrea, M. R., Brandt, M. R., Liu, Y., Flores, C. M., & Qin, N. (2007). Attenuated cold sensitivity in TRPM8 null mice. Neuron 54: 379-386.
Dhaka, A., Earley, T. J., Watson, J. & Papapoutian, A. (2008). Visualizing cold spots: TRPM8-expressing sensory neurons and their projections. J. Neurosci. 28: 566-575.
Dhaka, A., Murray, A. N., Mathur, J., Earley, T. J., Petrus, M. J. & Patapoutian, A. (2007). TRPM8 is required for cold sensation in mice. Neuron 54: 371-378.
Dhaka, A., Viswanath, V. & Papapoutian, A. (2006). TRP ion channels and temperature sensation. Annu. Rev. Neurosci. 29: 135-161.
Lumpkin, E. A. & Catarina, M. J. (2007). Mechanisms of sensory transduction in the skin. Nature 445: 858-865.
McKemy, D. D., Neuhausser, W. M. & Julius, D. (2002). Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature416: 52-58.
Peier, A. M., Moqrich, A., Hergarden, A. C., Reeve, A. J., Andersson, D. A., Story, G. M., Earley, T. J., Dragoni, I. McIntyre, P., Bevan, S. & Papapoutian, A. (2002). A TRP channel that senses cold stimuli and menthol. Cell108: 705-715.
Proudfoot, C. J., Garry, E. M., Cottrell, D. F., Rosie, R., Anderson, H., Robertson, D. C., Fleetwood-Walker, S. M. & Mitchell, R. (2006). Analgesia mediated by the TRPM8 cold receptor in chronic neuropathic pain. Curr. Biol. 16: 1591-1605.
Story, G. M., Peier, A. M., Reeve, A. J., Eid, S. R., Mosbacher, J., Hricik,. T. R., Earley, T. J., Hergarden, A. C., Andersson, D. A., Wook Hwang, S., McIntyre, P., Jegla, T., Bevan, S., & Papapoutian, A. (2003). ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures. Cell 112: 819-829.
Takashima, Y., Daniels, R. L. Knowlton, W., Teng, J., Liman, E. R. & McKemy, D. D. (2007). Diversity in the neuronal circuitry of cold sensing revealed by genetic labelling of Transient Receptor Potential Melastatin 8 neurons. J. Neurosci. 27: 14147-14157.
Voets, T., Droogmans, G., Wissenbach, U., Janssens, A., Flockerzi, V. & Nilius, B. (2004). The principle of temperature-dependent gating in cold- and heat-sensitive TRP channels. Nature 430: 748-754.