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A trio of ion channels takes the heat

Of the various temperature-sensitive ion channels identified previously, three have now been found to act in concert to detect painful heat and initiate protective reflexes.
Rose Z. Hill is in the Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, USA.
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Diana M. Bautista is in the Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, USA, and at the Helen Wills Neuroscience Institute, University of California, Berkeley.
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There’s nothing cosier than sitting by the fire on a cold night, and mammals have an amazing ability to find the perfect spot in which to warm themselves without being burnt. This ability is mediated by specialized heat-sensitive neurons of the somatosensory system that innervate the skin. These neurons are fine-tuned to detect the temperature at which pleasurable warmth turns into painful (noxious) heat, and are responsible for initiating protective reflexes and triggering avoidance behaviours. The search for temperature sensors in somatosensory neurons has uncovered several ion channels that are part of the transient receptor potential (TRP) family14, but the TRP channel or channels that are responsible for heat-evoked pain have remained unclear. In a paper in Nature, Vandewauw et al.5 report that three TRP channels work together to detect noxious heat in mice.

The first temperature-sensitive TRP channel, TRPV1, was discovered more than 20 years ago1. TRPV1 has a crucial role in the development of hypersensitivity to heat after injury or inflammation, but experiments have revealed that mice that lack TRPV1 display only a partial defect in the ability to sense and respond to noxious heat6. Another TRP channel in somatosensory neurons, TRPM3, is also activated in response to painful temperatures; however, heat-evoked pain-avoidance behaviours are only partially attenuated in mice that lack this channel3, leaving the mystery of how painful heat is sensed unsolved.

Vandewauw et al. report that double-mutant mice, which lack both the TRPV1 and TRPM3 channels, show only mild defects in heat-evoked pain-avoidance behaviours, similar to mice that lack just one of those channels. By contrast, they find that mice that lack a third channel, TRPA1, as well as TRPV1 and TRPM3, do not display any protective avoidance behaviours when exposed to noxious heat (Fig. 1). The three channels therefore act in concert to mediate behavioural responses to noxious heat.

Figure 1 | Three heat-sensitive TRP channels. Vandewauw et al.5 demonstrate in mice that potentially damaging temperatures excite pain-sensing neurons of the peripheral nervous system through the activity of three ion channels from the TRP family — TRPV1, TRPM3 and TRPA1. Activation of TRPA1 (by, for example, hydrogen peroxide, H2O2) is likely to require oxidation of certain amino-acid residues, as well as the presence of heat. Activation of the three channels causes neuronal firing and the transmission of signals to the central nervous system, leading to pain-associated behaviours and protective reflexes.

What led Vandewauw and colleagues to implicate TRPA1 in heat sensing? The authors observed that a subset of the heat-responsive somatosensory neurons that normally express TRPV1 and TRPM3 also express TRPA1, which has previously been shown to mediate inflammatory pain7 and itching8 in mice. TRPA1 is known to contribute to the heat-sensing abilities of non-mammalian organisms, including rattlesnakes9 and fruit flies10, but mice that lack TRPA1 exhibit normal avoidance of noxious heat7,11. Therefore, the protein has not been implicated in heat sensing in mammals — until now.

Activation of this channel by heat in rattlesnakes or fruit flies involves specialized sequences of amino acids known as ankyrin repeats at the amino terminus12. These repetitive stretches are different in mammalian TRPA1, making the channel insensitive to heat under normal conditions12. By contrast, activation of TRPA1 in mice by inflammatory molecules is dependent on the oxidation state of three cysteine amino-acid residues located adjacent to the ankyrin repeats13. Vandewauw and colleagues therefore proposed that oxidation of these residues might be sufficient to activate the heat-sensing capabilities of mouse TRPA1.

To trigger oxidation of TRPA1 in vitro, the authors applied hydrogen peroxide to sensory neurons that lacked TRPV1 and TRPM3 but expressed TRPA1. They found that hydrogen peroxide treatment did sensitize TRPA1 in such a way that heat could now excite the neurons. This suggests that mouse TRPA1 must be oxidized to respond to heat. However, the authors do not provide a physiological mechanism for how TRPA1 might be oxidized in vivo to participate in heat sensing. This will no doubt be an area for future investigation.

Vandewauw and colleagues also performed electrophysiological experiments, which revealed that the three TRP channels they studied are co-expressed in more than one class of somatosensory nerve fibre — including at least two types of pain-sensing neuron that encode distinct sensations, such as dull pain or sharp pain. The expression of these channels in different neuronal subtypes might give rise to complex circuitry and crosstalk that aids the rapid avoidance of noxious heat. In addition, it could add a further layer of redundancy to an important protective response.

Finally, the group showed that, although the triple-mutant mice do not exhibit protective heat-avoidance reflexes, they do have the same preference as control mice for innocuous warm temperatures (30 °C) over noxious high temperatures (45 °C) when presented with a choice. This finding suggests that the sensing of painful heat might not have a substantial role in determining a preference for pleasurable temperatures over painful ones, warranting further investigation of warmth sensing — an area of active debate. A previous study has shown that whereas heat-responsive spinal neurons, which receive input from heat-sensitive somatosensory neurons, respond to absolute temperatures, cold-responsive spinal neurons, which receive input from cold-sensitive somatosensory neurons, respond to relative changes in temperature14. Together, these data imply that the main role of peripheral heat-sensing neurons, such as those described by Vandewauw et al., might be to mediate avoidance of high temperatures, rather than to set an animal’s preferred temperature range.

Circuit-tracing and in vivo imaging will no doubt reveal the contributions of different subsets of peripheral neurons to the various representations of cold, cool, warm and hot temperatures in the central nervous system. Decoding these circuits will help to unravel the nuances of sensory perception and to elucidate the basis for diverse temperature preference between species or individual organisms.

Nature 555, 591-592 (2018)

doi: 10.1038/d41586-018-02663-1
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