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Identification of a cold receptor reveals a general role for TRP channels in thermosensation

Abstract

The cellular and molecular mechanisms that enable us to sense cold are not well understood. Insights into this process have come from the use of pharmacological agents, such as menthol, that elicit a cooling sensation. Here we have characterized and cloned a menthol receptor from trigeminal sensory neurons that is also activated by thermal stimuli in the cool to cold range. This cold- and menthol-sensitive receptor, CMR1, is a member of the TRP family of excitatory ion channels, and we propose that it functions as a transducer of cold stimuli in the somatosensory system. These findings, together with our previous identification of the heat-sensitive channels VR1 and VRL-1, demonstrate that TRP channels detect temperatures over a wide range and are the principal sensors of thermal stimuli in the mammalian peripheral nervous system.

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Figure 1: A subset of trigeminal neurons express an outwardly rectifying Ca2+-permeable channel activated by menthol and cold.
Figure 2: Cooling compounds activate the cloned receptor.
Figure 3: Electrophysiological properties of menthol-induced currents in transfected HEK293 cells.
Figure 4: The menthol receptor is sensitive to cold.
Figure 5: CMR1 is a member of the TRP family of ion channels.
Figure 6: CMR1 is expressed by small-diameter neurons in trigeminal and dorsal root ganglia.
Figure 7: TRP-like channels mediate thermosensation from cold to hot.

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Acknowledgements

We thank the members of our laboratory for encouragement, advice and assistance throughout this project. We are also grateful to R. Nicoll, H. Ingraham and A. Basbaum for advice and critical reading of the manuscript. D.D.M. was supported by a National Institutes of Health (NIH) postdoctoral training grant from the University of California—San Francisco (UCSF) Cardiovascular Research Institute and is a recipient of an Arthritis Foundation Postdoctoral Fellowship. W.M.N. was supported by a Fulbright scholarship and a NIH predoctoral training grant from the UCSF Biomedical Sciences Graduate Program. This work was supported by grants from the NIH to D.J.

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McKemy, D., Neuhausser, W. & Julius, D. Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature 416, 52–58 (2002). https://doi.org/10.1038/nature719

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