The menthol receptor TRPM8 is the principal detector of environmental cold

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Abstract

Sensory nerve fibres can detect changes in temperature over a remarkably wide range, a process that has been proposed to involve direct activation of thermosensitive excitatory transient receptor potential (TRP) ion channels1,2,3,4. One such channel—TRP melastatin 8 (TRPM8) or cold and menthol receptor 1 (CMR1)—is activated by chemical cooling agents (such as menthol) or when ambient temperatures drop below 26 °C, suggesting that it mediates the detection of cold thermal stimuli by primary afferent sensory neurons5,6. However, some studies have questioned the contribution of TRPM8 to cold detection or proposed that other excitatory or inhibitory channels are more critical to this sensory modality in vivo7,8,9,10. Here we show that cultured sensory neurons and intact sensory nerve fibres from TRPM8-deficient mice exhibit profoundly diminished responses to cold. These animals also show clear behavioural deficits in their ability to discriminate between cold and warm surfaces, or to respond to evaporative cooling. At the same time, TRPM8 mutant mice are not completely insensitive to cold as they avoid contact with surfaces below 10 °C, albeit with reduced efficiency. Thus, our findings demonstrate an essential and predominant role for TRPM8 in thermosensation over a wide range of cold temperatures, validating the hypothesis2 that TRP channels are the principal sensors of thermal stimuli in the peripheral nervous system.

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Figure 1: Generation and histological analysis of TRPM8-deficient mice.
Figure 2: TRPM8-deficient neurons show loss of menthol and cold sensitivity.
Figure 3: TRPM8-deficient nerve fibres show loss of cold sensitivity.
Figure 4: TRPM8 is required for normal cold-evoked behaviours.

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Acknowledgements

We thank R. Nicoll for discussion and criticism, M. Tominaga for providing TRPM8 antiserum, T. Nikai for advice regarding behavioural assays, and J. Poblete for technical assistance throughout. This work was supported by grants from the NIH (D.J., A.I.B., S.-E.J. and C.L.S.), a Burroughs Welcome Fund Career Award in Biomedical Sciences (D.M.B.) and a postdoctoral fellowship from the International Human Frontier Science Program Organization (J.S.).

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Correspondence to Cheryl L. Stucky or David Julius.

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Supplementary information

Supplementary Figures 1-4 with Legends and Supplementary Table 1

Supplementary Figure 1 shows RT-PCR analysis and in situ hybridization of TRPM8. The prevalence of neurons that normally would express TRPM8 in trigeminal ganglia has not changed in the TRPM8-/- littermates. Supplementary Figure 2 shows properties of C and AM fibers assessed using the skin-nerve preparation. Basal firing rates of sensory nerve fibers from TRPM8-deficient mice were substantially reduced compared to wild type controls. However all other electrical and mechanical properties of these fibers were unaltered by TRPM8 disruption. Supplementary Figure 3 shows mechanical and thermal (heat) thresholds for wild type and TRPM8-deficient littermates as determined by Von Frey filament and radiant heat behavioral paradigms, respectively. Similar responses were observed for both genotypes. Supplementary Figure 4 demonstrates that TRPA1-deficient mice have normal cold sensitivity, irrespective of whether male or female mice (not in estrus) were examined. Supplementary Table 1 shows that DRG and TG neurons from wild type or TRPM8-/- mice respond similarly to a variety of different chemical and thermal stimuli, irrespective of genotype. (PDF 482 kb)

Supplementary Video

This file contains Supplementary Video 1. This movie shows a representative two-plate choice test in which wild type or TRPM8-deficient mice are examined for exploratory behavior with surface temperatures adjusted to 30°C and 20°C, as shown. It is evident that the TRPM8-deficient mouse exhibits no preference for the warmer side during the 30 sec exploratory period, whereas the wild type littermate spends most of its time at 30°C. Moreover, the wild type mouse shows clear aversion to the colder side. (MOV 3376 kb)

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Bautista, D., Siemens, J., Glazer, J. et al. The menthol receptor TRPM8 is the principal detector of environmental cold. Nature 448, 204–208 (2007) doi:10.1038/nature05910

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