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ThermoTRP channels and cold sensing: what are they really up to?

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Abstract

Cooling is sensed by peripheral thermoreceptors, the main transduction mechanism of which is probably a cold- and menthol-activated ion channel, transient receptor potential (melastatin)-8 (TRPM8). Stronger cooling also activates another TRP channel, TRP (ankyrin-like)-1, (TRPA1), which has been suggested to underlie cold nociception. This review examines the roles of these two channels and other mechanisms in thermal transduction. TRPM8 is activated directly by gentle cooling and depolarises sensory neurones; its threshold temperature (normally ~26–31°C in native neurones) is very flexible and it can adapt to long-term variations in baseline temperature to sensitively detect small temperature changes. This modulation is enabled by TRPM8’s low intrinsic thermal sensitivity: it is sensitised to varying degrees by its cellular context. TRPM8 is not the only thermosensitive element in cold receptors and interacts with other ionic currents to shape cold receptor activity. Cold can also cause pain: the transduction mechanism is uncertain, possibly involving TRPM8 in some neurones, but another candidate is TRPA1 which is activated in expression systems by strong cooling. However, native neurones that appear to express TRPA1 respond very slowly to cold, and TRPA1 alone cannot account readily for cold nociceptor activity or cold pain in humans. Other, as yet unknown, mechanisms of cold nociception are likely.

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Acknowledgements

Work in the author’s laboratory is supported by the Volkswagen Foundation, the Physiological Society and the Wellcome Trust. I am grateful to Alexandru Babes and Sally Lawson for comments on the manuscript, Felix Viana and Hans Braun for thought-provoking discussions, David Julius and David McKemy for rat TRPM8 used in the experiments shown in Fig. 4, and to Catriona Reid for help with preparing the figures.

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  1. Department of Animal Physiology and Biophysics Faculty of Biology, University of Bucharest, Splaiul Independenţei 91–95, 76201, Bucharest, Romania

    Gordon Reid

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A very recent study (Rohacs et al., Nature Neurosci 8:626-634, 2005) has considerably strengthened the evidence for involvement of PIP2 in Ca2+-dependent adaptation and modulation of TRPM8, making it likely that PIP2 has a dominant role in these processes.

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Reid, G. ThermoTRP channels and cold sensing: what are they really up to?. Pflugers Arch - Eur J Physiol 451, 250–263 (2005). https://doi.org/10.1007/s00424-005-1437-z

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