TRPM8

79054171382ENSG00000144481ENSMUSG00000036251Q7Z2W7Q8R4D5NM_024080NM_134252NP_076985NP_599013Transient receptor potential cation channel subfamily M (melastatin) member 8 (TRPM8), also known as the cold and menthol receptor 1 (CMR1), is a protein that in humans is encoded by the TRPM8 gene. The TRPM8 channel is the primary molecular transducer of cold somatosensation in humans. Transient receptor potential cation channel subfamily M (melastatin) member 8 (TRPM8), also known as the cold and menthol receptor 1 (CMR1), is a protein that in humans is encoded by the TRPM8 gene. The TRPM8 channel is the primary molecular transducer of cold somatosensation in humans. The TRPM8 channel is a homotetramer, composed of four identical subunits with a transmembrane domain with six helices (S1–6). The first four, S1–4, act as the voltage sensor and allow binding of menthol, icilin and similar channel agonists. S5 and S6 and a connecting loop, also part of the structure, make up the pore, a non-selective cation channel which consists of a highly conserved hydrophobic region, A range of diverse components are required for the high level of specificity in responding to result in ion flow to cold and menthol stimuli. TRPM8 is an ion channel, upon activation it allows the entry of Na+ and Ca2+ ions to the cell that leads to depolarization and the generation of an action potential. The signal is conducted from primary afferents (type C- and A-delta) eventually leading to the sensation of cold and cold pain. The TRPM8 protein is expressed in sensory neurons, and it is activated by cold temperatures and cooling agents, such as menthol and icilin whereas WS-12 and CPS-369 are the most selective agonists of TRPM8. TRPM8 is also expressed in the prostate, lungs, and bladder where its function is not well understood. The transient receptor potential channel (TRP) superfamily, which includes the menthol (TRPM8) and capsaicin receptors (TRPV1), serve a variety of functions in the peripheral and central nervous systems. In the peripheral nervous system, TRPs respond to stimuli from temperature, pressure, inflammatory agents, and receptor activation. Central nervous system roles of the receptors include neurite outgrowth, receptor signaling, and excitoxic cell death resulting from noxious stimuli. McKemy et al., 2002 provided some of the first evidence for existence of a cold-activated receptor throughout the mammalian somatosensory system. Using calcium imaging and patch clamp based approaches, they showed a response in dorsal root ganglion (DRG) neurons that exposure to cold, 20 °C or cooler, lead to a response in calcium influx. This receptor was shown to respond to both cold temperatures, menthol, and similar now-known agonists of the TRPM8 receptor. It works in conjunction with the TRPV1 receptor to maintain a feasible threshold temperature range in which our cells are comfortable and our perception of these stimuli occurs at the spinal cord and brain, which integrate signals from different fibers of varying sensitivity to temperature. Application of menthol to skin or mucus membranes results directly in membrane depolarization, followed by calcium influx via voltage-dependent calcium channels, providing evidence for the role of TRPM8 and other TRP receptors to mediate our sensory interaction with the environment in response to cold in the same way as in response to menthol. In contrast to the TRPV1 (capsaicin) receptor, which is potentiated by low pH, acidic conditions were shown to inhibit the TRPM8 Ca2+ response to menthol and icilin (an agonist of the menthol receptor). It is hypothesized the TRPV1 and TRPM8 receptors act together in response to inflammatory conditions: TRPV1, by proton action, increases the burning sensation of pain, while the acidity inhibits TRPM8 to block the more pleasant sensation of coolness in more dire instances of pain. Numerous studies have been published investigating the effect of L-menthol application as a model for TRPM8-sensitization. The primary consensus finding is that TRPM8 sensitization increases the sensation of cold pain, also known as cold hyperalgesia. An experiment was done in a double-blind two-way crossover study by applying 40% L-menthol to the forearm, using ethanol as a control. Activation of the TRPM8-receptor channel (the primary menthol receptor channel) resulted in increased sensitization to the menthol stimulus. To investigate the mechanisms of this sensitization, Wasner et al., 2004, performed A fiber conduction blockade of the superficial radial nerve in another group of subjects. This ended up reducing the menthol-induced sensation of cold and hyperalgesia because blocking A fiber conduction resulted in inhibition of a class of group C nerve fiber nociceptors needed to transduce the sensation of pain. They concluded menthol sensitizes cold-sensitive peripheral C nociceptors and activates cold-specific A delta fibers.