The molecular and cellular basis of thermosensation in mammals

Abstract

Over a decade and a half of intensive study has shown that the Transient Receptor Potential family ion channels TRPV1 and TRPM8 are the primary sensors of heat and cold temperatures in the peripheral nervous system. TRPV homologues and TRPA1 are also implicated, but recent genetic evidence has diminished their significance in thermosensation and suggests that a number of newly identified thermosensitive channels, including TRPM3, two-pore potassium channels, and the chloride channel Ano1, require further consideration. In addition to novel thermostransducers, recent genetic and pharmacological approaches have begun to elucidate the afferent neurocircuits underlying temperature sensation, continuing the rapid expansion in our understanding of the cellular and molecular basis of thermosensation that began with the discovery of TRPV1 and TRPM8.

Figure 1. Molecules mediating thermosensation

The sensations of heat and cold are transduced by distinct subsets of sensory neurons characterized by their expression of TRPV1 and TRPM8, respectively. Ion channels like TRPM3 and ANO1 also contribute to heat detection. Similarly, TRPM8-independent molecular mechanisms of cold-sensitivity include cold-activated channels like TRPC5. Even though the role of the TRPA1 channel as a cold sensor is controversial, it contributes to cold hypersensitivity in pathological conditions. Furthermore, the differential expression of Na⁺ and K⁺ channels, like Nav1.6, Nav1.8, TREK1/2, TRAAK and TASK3 modulates the temperature thresholds of TRPV1- and TRPM8-expressing sensory afferents. In addition to neurons, keratinocytes expressing the temperature-sensitive TRPV3 and TRPV4 channels may contribute, but recent evidence questions their role in thermosensation.

Figure 2. Mechanisms of thermal hypersensitivity

Proalgesic agents, released from epithelium or immune cells or from nerve terminals neurogenically, modulate neuron activity by binding to their receptors, which then influence neuron activity through downstream effects. TRPV1 mediates heat hyperalgesia by becoming sensitized downstream of a large number of inflammatory mediators. TRPA1 is involved in heat, cold and mechanical hyperalgesia after injury, both by being activated by channel agonists and by perpetuating neurogenic inflammation. TRPM8/TRPV1 co-expressing neurons are sensitized to cold by NGF and artemin, while non-TRPV1 expressing TRPM8 neurons (involved in sensing innocuous cool and cold-mediated analgesia) are inhibited by certain inflammatory mediators. Cold hyperalgesia also occurs as a result of the downregulation of “excitability breaks” such as the K2P class of K⁺ channels.