Cannabinoid non-cannabidiol site modulation of TRPV2 structure and function

Liying Zhang, Charlotte Simonsen, Lucie Zimova, Kaituo Wang, Lavanya Moparthi, Rachelle Gaudet, Maria Ekoff, Gunnar Nilsson, Ute A. Hellmich, Viktorie Vlachova, Pontus Gourdon () and Peter M. Zygmunt ()
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Liying Zhang: Lund University
Charlotte Simonsen: Lund University
Lucie Zimova: Czech Academy of Sciences
Kaituo Wang: University of Copenhagen
Lavanya Moparthi: Linköping University
Rachelle Gaudet: Harvard University
Maria Ekoff: Karolinska University Hospital
Gunnar Nilsson: Karolinska University Hospital
Ute A. Hellmich: Friedrich Schiller University Jena
Viktorie Vlachova: Czech Academy of Sciences
Pontus Gourdon: Lund University
Peter M. Zygmunt: Lund University

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract 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 Δ9-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.

Date: 2022
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DOI: 10.1038/s41467-022-35163-y

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