Ion channels involved in cold detection in mammals: TRP and non-TRP mechanisms

Abstract

Substantial progress in understanding thermal transduction in peripheral sensory nerve endings was achieved with the recent cloning of six thermally gated ion channels from the TRP (transient receptor potential) super-family. Two of these channels, TRP melastatin 8 (TRPM8) and TRP ankyrin 1 (TRPA1), are expressed in dorsal root ganglion (DRG) and trigeminal ganglion (TG) neurons, are activated by various degrees of cooling, and are candidates for mediating gentle cooling and noxious cold, respectively. However, accumulating evidence suggests that more than just these two channels are involved in cold sensing in mammals. A recent report described a critical role of the voltage-gated tetrodotoxin-resistant sodium channel Na v 1.8 in perceiving intense cold and noxious stimuli at cold temperatures. Other ion channels, such as two-pore domain background potassium channels (K2P), are known to be expressed in peripheral nerves, have pronounced temperature dependence, and may contribute to cold sensing and/or cold hypersensitivity in pain states. This article reviews the evidence supporting a role for each of these channels in cold transduction, focusing on their biophysical properties, expression pattern, and modulation by pro-inflammatory mediators.

Nociceptors: the sensors of the pain pathway

“…Cooling the skin to 4°C activates A- and C-fibers sensitive to innocuous cooling and cold-sensitive nociceptors (27-29, 67, 69), consistent with the presence of two populations of cold-sensitive neurons observed in culture (70)(71)(72). Cool-sensitive nonnociceptive afferents are spontaneously active at normal skin temperature and their excitability increases with decreasing temperature (53,67).…”

Efficient entry of cell-penetrating peptide nona-arginine into adherent cells involves a transient increase in intracellular calcium

“…Indeed, we observed a significant decrease in the fraction of R 9 -TAMRA-positive cells in the presence of the non-selective cation channel inhibitors La 3+ and ruthenium red ( Figure 7 A). Since members of the TRP family of non-selective cation channels, namely TRPA1 and TRPM8, have been implicated in cold sensing in vivo and demonstrate a cold-activated current response in vitro [ 29 , 30 ], we assessed their involvement in cold-induced R 9 -TAMRA entry. Neither specific antagonists of TRPA1 HC030031 and AP18 nor specific antagonists of TRPM8 channel AMTB inhibited cold-induced entry of R 9 -TAMRA ( Figure 7 B).…”

Axonal thermosensitivity and mechanosensitivity of cutaneous afferent neurons

“…In fact, many afferent cold‐sensitive neurons do not express either the TRPM8 or the TRPA1 protein, and it is suggested that several other channels, in particular potassium channels, may be involved in the responses of afferent neurons to cold stimuli (Munns et al. , 2007; Babes, 2009).…”