0565702 - FGÚ 2023 RIV GB eng J - Journal Article
Zhang, L. - Simonsen, Ch. - Zímová, Lucie - Wang, K. - Moparthi, L. - Gaudet, R. - Ekoff, M. - Nilsson, G. - Hellmich, U. A. - Vlachová, Viktorie - Gourdon, P. - Zygmunt, P. M.
Cannabinoid non-cannabidiol site modulation of TRPV2 structure and function.
Nature Communications. Roč. 13, č. 1 (2022), č. článku 7483. ISSN 2041-1723. E-ISSN 2041-1723
R&D Projects: GA ČR(CZ) GA22-13750S
Institutional support: RVO:67985823
Keywords : TRPV cation channels * cannabinoids * cannabidiol * ligand * TRPV2 protein
OECD category: Neurosciences (including psychophysiology
Impact factor: 16.6, year: 2022 ; AIS: 5.767, rok: 2022
Method of publishing: Open access
Result website:
https://doi.org/10.1038/s41467-022-35163-yDOI: https://doi.org/10.1038/s41467-022-35163-y

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 delta9-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.
Permanent Link: https://hdl.handle.net/11104/0337220