Structural highlights
Function
TRPM8_MOUSE Receptor-activated non-selective cation channel involved in detection of sensations such as coolness, by being activated by cold temperature below 25 degrees Celsius. Activated by icilin, eucalyptol, menthol, cold and modulation of intracellular pH. Involved in menthol sensation. Permeable for monovalent cations sodium, potassium, and cesium and divalent cation calcium. Temperature sensing is tightly linked to voltage-dependent gating. Activated upon depolarization, changes in temperature resulting in graded shifts of its voltage-dependent activation curves. The chemical agonists menthol functions as a gating modifier, shifting activation curves towards physiological membrane potentials. Temperature sensitivity arises from a tenfold difference in the activation energies associated with voltage-dependent opening and closing.[1] [2]
Publication Abstract from PubMed
Our sensory adaptation to cold and chemically induced coolness is mediated by the intrinsic property of TRPM8 channels to desensitize. TRPM8 is also implicated in cold-evoked pain disorders and migraine, highlighting its inhibitors as an avenue for pain relief. Despite the importance, the mechanisms of TRPM8 desensitization and inhibition remained unclear. We found, using cryo-electron microscopy, electrophysiology, and molecular dynamics simulations, that TRPM8 inhibitors bind selectively to the desensitized state of the channel. These inhibitors were used to reveal the overlapping mechanisms of desensitization and inhibition and that cold and cooling agonists share a common desensitization pathway. Furthermore, we identified the structural determinants crucial for the conformational change in TRPM8 desensitization. Our study illustrates how receptor-level conformational changes alter cold sensation, providing insights into therapeutic development.
Mechanisms of sensory adaptation and inhibition of the cold and menthol receptor TRPM8.,Yin Y, Park CG, Zhang F, G Fedor J, Feng S, Suo Y, Im W, Lee SY Sci Adv. 2024 Aug 2;10(31):eadp2211. doi: 10.1126/sciadv.adp2211. Epub 2024 Aug , 2. PMID:39093967[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Peier AM, Moqrich A, Hergarden AC, Reeve AJ, Andersson DA, Story GM, Earley TJ, Dragoni I, McIntyre P, Bevan S, Patapoutian A. A TRP channel that senses cold stimuli and menthol. Cell. 2002 Mar 8;108(5):705-15. doi: 10.1016/s0092-8674(02)00652-9. PMID:11893340 doi:http://dx.doi.org/10.1016/s0092-8674(02)00652-9
- ↑ Andersson DA, Chase HW, Bevan S. TRPM8 activation by menthol, icilin, and cold is differentially modulated by intracellular pH. J Neurosci. 2004 Jun 9;24(23):5364-9. doi: 10.1523/JNEUROSCI.0890-04.2004. PMID:15190109 doi:http://dx.doi.org/10.1523/JNEUROSCI.0890-04.2004
- ↑ Yin Y, Park CG, Zhang F, G Fedor J, Feng S, Suo Y, Im W, Lee SY. Mechanisms of sensory adaptation and inhibition of the cold and menthol receptor TRPM8. Sci Adv. 2024 Aug 2;10(31):eadp2211. PMID:39093967 doi:10.1126/sciadv.adp2211
