Cannabinoid non-cannabidiol site modulation of TRPV2 structure and function

0565702 - FGÚ 2023 RIV GB eng J - Článek v odborném periodiku
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. E-ISSN 2041-1723
Grant CEP: GA ČR(CZ) GA22-13750S
Institucionální podpora: RVO:67985823
Klíčová slova: TRPV cation channels * cannabinoids * cannabidiol * ligand * TRPV2 protein
Obor OECD: Neurosciences (including psychophysiology
Impakt faktor: 16.6, rok: 2022
Způsob publikování: Open access
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.
Trvalý link: https://hdl.handle.net/11104/0337220