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

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 approximately 26-31 degrees 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.