The Role of Cold-Sensitive Ion Channels in Peripheral Thermosensation

Abstract

The detection of ambient cold is critical for mammals, who use this information to avoid tissue damage by cold and to maintain stable body temperature. The transduction of information about the environmental cold is mediated by cold-sensitive ion channels expressed in peripheral sensory nerve endings in the skin. Most transduction mechanisms for detecting temperature changes identified to date depend on transient receptor potential (TRP) ion channels. Mild cooling is detected by the menthol-sensitive TRPM8 ion channel, but how painful cold is detected remains unclear. The TRPA1 ion channel, which is activated by cold in expression systems, seemed to provide an answer to this question, but whether TRPA1 is activated by cold in neurons and contributes to the sensation of cold pain continues to be a matter of debate. Recent advances have been made in this area of investigation with the identification of several potential cold-sensitive ion channels in thermosensory neurons, including two-pore domain potassium channels (K2P), GluK2 glutamate receptors, and CNGA3 cyclic nucleotide-gated ion channels. This mini-review gives a brief overview of the way by which ion channels contribute to cold sensation, discusses the controversy around the cold-sensitivity of TRPA1, and provides an assessment of some recently-proposed novel cold-transduction mechanisms. Evidence for another unidentified cold-transduction mechanism is also presented.

Keywords: CNGA3; ENaC; GluK2; K2P; TRPA1; TRPC5; TRPM8; cold sensation.

Figure 1

Overview of molecular mechanisms that have been proposed to underlie responses to cold in primary somatosensory neurons. Bottom left: potential sensory mechanisms triggered by mild non-noxious cooling, down to around 23°C, include TRPC5 [‘Transient Receptor Potential Canonical 5 (TRPC5) ” section], TRPM8 [“Transient Receptor Potential Melastatin 8 (TRPM8)” section], ENaC channels [“Epithelial Sodium Channels (ENaC)” section] and members of the K2P two-pore potassium channel family [“Two-Pore Domain Potassium Channels (K2P)” section]. Bottom middle: the cyclic nucleotide-gated channel CNGA3 has been proposed to be activated by cold down to 22°C [“Cyclic Nucleotide-Gated Channel Alpha 3 (CNGA3)” section]. Bottom right: noxious cold below 22°C has been proposed to activate TRPA1 [“Transient Receptor Potential Ankyrin 1 (TRPA1)” section], possibly via activation of an unknown channel (see arrows]. A recent article proposes that the glutamate receptor GluK2 [“Glutamate Ionotropic Receptor Kainate Type Subunit 2 (GluK2)” section] may trigger cold responses that are G-protein mediated, possibly by modulating an unknown channel (see arrows). Top right: expression of the Nav1.8 sodium channel may allow the cold sensation to continue down to very low temperatures (“Modulation of Cold Responses by Background Potassium Currents” section). Top left: sensory neuronal excitability can be modulated by the activity of members of the Kv1 potassium channel family, which are not directly cold-sensitive themselves (“Mechanisms Transmitting Cold Responses” section).