ThermoTRP channels and beyond: mechanisms of temperature sensation

Key Points

  • The identification of a family of transient receptor potential (TRP) ion channels that are gated by specific temperatures has been an important advance in the elucidation of the molecular mechanisms of thermosensitivity.

  • Hot temperatures in the noxious range (≥ 42°C) activate the channels Trpv1 and Trpv2. Trpv1 is also activated by low pH and by capsaicin, whereas Trpv2, which has a higher activation threshold, is not.

  • Warm temperatures in the innocuous range (34–42°C) activate the channels Trpv3 and Trpv4. Although the activation properties of these channels parallel the behaviour of the relevant afferent sensory fibres, there is no evidence yet for a functional role of Trpv3 and Trpv4 in vivo.

  • Cool and cold temperatures activate the channels Trpv8 and Anktn1. Trpm8 is also activated by menthol, whereas the activation threshold of Anktm1 is set at temperatures that humans tend to regard as painfully cold.

  • According to the labelled-line hypothesis, distinct sets of sensory neurons are tuned to convey specific sensory information through dedicated pathways to the central nervous system. However, the exact connectivity between the primary thermoreceptors and their spinal interneuron targets is not clear. It will be important to establish whether the pattern of expression of the different thermoTRPs sheds light on the organization of those dedicated pathways.

  • Another enigma concerns the gating mechanism of thermoTRPs by hot or cold temperatures. Although their interaction with cytoplasmic elements has been proposed to be important, the evidence is still incomplete.

  • In addition to thermoTRPs, other mechanisms for thermosensation have been put forward, They include the inhibition of background potassium conductances (perhaps the TREK-1 channel) or of a Na+/K+ ATPase, or the activation of pH-sensitive channels such as ASIC and DRASIC.

  • In invertebrates, the neuroanatomy of thermosensation is partially understood, but the molecular mechanisms remain to be elucidated. Recent evidence indicates that TRP channels might also be involved in these organisms.

  • An important development in this field will be the generation of mice that lack the different thermoTRPs, as they will make it possible to establish their function in vivo.

Abstract

We possess an acute sense of temperature. Most of us seek shade on a hot summer day, prefer a warm shower to a cold one, and enjoy red wines served at a temperature of 15–18°C. Thermosensation not only affects our comfort, but is also essential for the survival of most organisms. We are now beginning to uncover the molecular identity of proteins that confer thermosensation. The thermoTRPs, a subset of transient receptor potential ion channels are activated by distinct physiological temperatures, and are involved in converting thermal information into chemical and electrical signals within the sensory nervous system.

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Figure 1: Anatomic and functional organization of touch.
Figure 2: Average discharge frequency of individual cold- and warm-sensitive fibres in response to changes in skin temperature.
Figure 3: Domain organization and temperature thresholds of temperature-activated transient receptor potential ion channels (thermoTRPs).
Figure 4: Expression and temperature sensitivity of temperature-activated transient receptor potential ion channels (thermoTRPs) label distinct populations of sensory neurons.

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Acknowledgements

We thank N. Hong, T. Jegla, U. Mueller and L. Stowers for critically reading the manuscript.

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Correspondence to Ardem Patapoutian.

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DATABASES

Flybase

painless

LocusLink

Anktm1

Trpm8

Trpv1

Trpv2

Trpv3

Trpv4

Glossary

PROPRIOCEPTORS

Sensory terminals that are present in muscles, tendons and joint capsules, which receive information about the movements and position of the body.

ANKYRIN

A protein domain that attaches integral membrane proteins to cytoskeletal elements.

Q10

The change in the rate of activity resulting from a 10°C increase in temperature. The higher the Q10, the more sensitive to temperature the reaction is.

HYPERALGESIA

Repeated application of a noxious stimulus leads to a progressive increase in the response of nociceptors. This process, known as hyperalgesia, manifests as a prolonged pain sensation even after the stimulus is removed.

NORTHERN BLOT

A molecular technique in which RNA molecules are separated by electrophoresis, transferred to nitrocellulose, and subsequently identified with a suitable probe.

PARADOXICAL HEAT AND COLD

Conditions in which a cold stimulus produces the sensation of being hot and vice versa.

THERMAL GRILL ILLUSION

A sensation of painful heat that is elicited by touching interlaced warm and cool bars. It was first shown by T. Thunberg in 1896.

ALLODYNIA

A heightened sensitivity to a normally innocuous stimulus such that it is perceived as painful. An example is an increased sensitivity of sunburned skin to light touch.

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Patapoutian, A., Peier, A., Story, G. et al. ThermoTRP channels and beyond: mechanisms of temperature sensation. Nat Rev Neurosci 4, 529–539 (2003). https://doi.org/10.1038/nrn1141

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