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-Structure paper
タイトル | Mechanisms of sensory adaptation and inhibition of the cold and menthol receptor TRPM8. |
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ジャーナル・号・ページ | Sci Adv, Vol. 10, Issue 31, Page eadp2211, Year 2024 |
掲載日 | 2024年8月2日 |
![]() | Ying Yin / Cheon-Gyu Park / Feng Zhang / Justin G Fedor / Shasha Feng / Yang Suo / Wonpil Im / Seok-Yong Lee / ![]() |
PubMed 要旨 | 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 ...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. |
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手法 | EM (単粒子) |
解像度 | 2.76 - 4.13 Å |
構造データ | EMDB-44255, PDB-9b6d: EMDB-44256, PDB-9b6e: EMDB-44257, PDB-9b6f: EMDB-44258, PDB-9b6g: EMDB-44259, PDB-9b6h: EMDB-44260, PDB-9b6i: EMDB-44261, PDB-9b6j: EMDB-44262, PDB-9b6k: |
化合物 | ![]() ChemComp-Y01: ![]() ChemComp-T14: ![]() PDB-1aiy: ![]() ChemComp-LQ7: ![]() ChemComp-NAG: ![]() ChemComp-ULO: ![]() ChemComp-CA: ![]() ChemComp-PIO: |
由来 |
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![]() | MEMBRANE PROTEIN / TRPM8 / menthol receptor / cold receptor / PI(4 / 5)P2 / cooling agonists / temperature sensing / ion channel / sensory transduction / transient receptor potential ion channel / TRPM8 activation / TRPM8 inhibition / TRPM8 desensitization / TRPM8 antagonists |