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TitleMechanisms of sensory adaptation and inhibition of the cold and menthol receptor TRPM8.
Journal, issue, pagesSci Adv, Vol. 10, Issue 31, Page eadp2211, Year 2024
Publish dateAug 2, 2024
AuthorsYing Yin / Cheon-Gyu Park / Feng Zhang / Justin G Fedor / Shasha Feng / Yang Suo / Wonpil Im / Seok-Yong Lee /
PubMed AbstractOur 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.
External linksSci Adv / PubMed:39093967 / PubMed Central
MethodsEM (single particle)
Resolution2.76 - 4.13 Å
Structure data

44255

9b6d

EMDB-44255, PDB-9b6d:
Cryo-EM structure of the mouse TRPM8 channel in the ligand-free desensitized state
Method: EM (single particle) / Resolution: 3.3 Å

44256

9b6e

EMDB-44256, PDB-9b6e:
Cryo-EM structure of the mouse TRPM8 channel in complex with the antagonist TC-I 2014
Method: EM (single particle) / Resolution: 2.91 Å

44257

9b6f

EMDB-44257, PDB-9b6f:
Cryo-EM structure of the mouse TRPM8 channel in complex with the antagonist AMG2850
Method: EM (single particle) / Resolution: 3.42 Å

44258

9b6g

EMDB-44258, PDB-9b6g:
Cryo-EM structure of the mouse TRPM8 channel in complex with the antagonist AMTB
Method: EM (single particle) / Resolution: 2.81 Å

44259

9b6h

EMDB-44259, PDB-9b6h:
Cryo-EM structure of the mouse TRPM8 channel in complex with the antagonist TC-I 2014 and the cooling agonist C3
Method: EM (single particle) / Resolution: 2.76 Å

44260

9b6i

EMDB-44260, PDB-9b6i:
Cryo-EM structure of the avian great tit TRPM8 channel in complex with the antagonist TC-I 2014
Method: EM (single particle) / Resolution: 3.26 Å

44261

9b6j

EMDB-44261, PDB-9b6j:
Cryo-EM structure of the mouse TRPM8 channel in complex with PI(4,5)P2 and Ca2+
Method: EM (single particle) / Resolution: 3.53 Å

44262

9b6k

EMDB-44262, PDB-9b6k:
Cryo-EM structure of the mouse TRPM8 channel in complex with Ca2+ in the absence of PI(4,5)P2
Method: EM (single particle) / Resolution: 4.13 Å

Chemicals

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

ChemComp-T14:
3-{7-(trifluoromethyl)-5-[2-(trifluoromethyl)phenyl]-1H-benzimidazol-2-yl}-1-oxa-2-azaspiro[4.5]dec-2-ene

PDB-1aiy:
R6 HUMAN INSULIN HEXAMER (SYMMETRIC), NMR, 10 STRUCTURES

ChemComp-LQ7:
N-(3-aminopropyl)-2-[(3-methylphenyl)methoxy]-N-[(thiophen-2-yl)methyl]benzamide

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

ChemComp-ULO:
nonyl(oxo)di(propan-2-yl)-lambda~5~-phosphane

ChemComp-CA:
Unknown entry

ChemComp-PIO:
[(2R)-2-octanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phosphoryl]oxy-propyl] octanoate

Source
  • mus musculus (house mouse)
  • parus major (Great Tit)
KeywordsMEMBRANE 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

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