期刊
NATURE COMMUNICATIONS
卷 13, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-022-35163-y
关键词
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资金
- Swedish Research Council [2014-3801, 2020-01693, 2016-04474]
- Medical Faculty of Lund University - ALF [ALFSKANE-451751]
- Hjaernfonden/the Swedish Brain Foundation [FO2020-0188, FO2022-0292]
- Stiftelsen Olle Engkvist Byggmaestare [189-290]
- Albert Pahlssons stiftelse
- Alfred OEsterlunds stiftelse
- Knut och Alice Wallenbergs Stiftelse [2015.0131, 2020.0194]
- Lundbeck Foundation [R133-A12689, R313-2019-774, R346-2020-2019]
- Danish Council for Independent Research [9039-00273]
- Crafoord Foundation [20170818]
- Czech Science Foundation [22-13750S]
- DFG Cluster of Excellence [EXC2051, 390713860]
- DFG Collaborative Research Center [1507, 450648163]
- National Institutes of Health [R01GM081340]
- Knut and Alice Wallenberg, Family Erling Persson and Kempe Foundations
- SciLifeLab
- Umea University
- Novo-Nordisk Foundation [NNF14CC0001]
- Vinnova [2016-04474] Funding Source: Vinnova
- Swedish Research Council [2016-04474, 2020-01693] Funding Source: Swedish Research Council
This study uses cryo-EM and electrophysiology to identify a cannabinoid binding site in TRPV2 that is distinct from cannabidiol, which could potentially be a drug target for the treatment of inflammation and immune-mediated diseases.
TRPV2 is a ligand-operated temperature sensor with poorly defined pharmacology. Here, we combine calcium imaging and patch-clamp electrophysiology with cryo-electron microscopy (cryo-EM) to explore how TRPV2 activity is modulated by the phytocannabinoid Delta(9)-tetrahydrocannabiorcol (C16) and by probenecid. C16 and probenecid act in concert to stimulate TRPV2 responses including histamine release from rat and human mast cells. Each ligand causes distinct conformational changes in TRPV2 as revealed by cryo-EM. Although the binding for probenecid remains elusive, C16 associates within the vanilloid pocket. As such, the C16 binding location is distinct from that of cannabidiol, partially overlapping with the binding site of the TRPV2 inhibitor piperlongumine. Taken together, we discover a new cannabinoid binding site in TRPV2 that is under the influence of allosteric control by probenecid. This molecular insight into ligand modulation enhances our understanding of TRPV2 in normal and pathophysiology. TRPV2 is activated by temperature and cannabinoids. Here, the authors have used cryo-EM and electrophysiology to identify a cannabinoid binding site distinct from that of cannabidiol as a possible drug target for treatment of inflammation and immune-mediated diseases.
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