Mechanisms of sensory adaptation and inhibition of the cold and menthol receptor TRPM8

被引：7

作者：

Yin, Ying ^{[1
]}

Park, Cheon-Gyu ^{[1
]}

Zhang, Feng ^{[1
]}

Fedor, Justin G. ^{[1
]}

Feng, Shasha ^{[2
]}

Suo, Yang ^{[1
]}

Im, Wonpil ^{[2
]}

Lee, Seok-Yong ^{[1
]}

机构：

[1] Duke Univ, Sch Med, Dept Biochem, Durham, NC 27710 USA

[2] Lehigh Univ, Dept Biol Sci, Bethlehem, PA 18015 USA

来源：

SCIENCE ADVANCES | 2024年 / 10卷 / 31期

基金：

美国国家卫生研究院;

关键词：

GUI MEMBRANE-BUILDER; BEAM-INDUCED MOTION; FORCE-FIELD; CHANNELS; VALIDATION; LIGAND; DESENSITIZATION; ANTAGONIST; DISCOVERY; TOOLS;

D O I：

10.1126/sciadv.adp2211

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：16

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