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Cannabinoid non-cannabidiol site modulation of TRPV2 structure and function

Zhang, Liying LU ; Simonsen, Charlotte LU ; Zimova, Lucie ; Wang, Kaituo ; Moparthi, Lavanya LU ; Gaudet, Rachelle ; Ekoff, Maria ; Nilsson, Gunnar LU ; Hellmich, Ute A. and Vlachova, Viktorie , et al. (2022) In Nature Communications 13.
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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Communications
volume
13
article number
7483
publisher
Nature Publishing Group
external identifiers
  • pmid:36470868
  • scopus:85143312444
ISSN
2041-1723
DOI
10.1038/s41467-022-35163-y
language
English
LU publication?
yes
additional info
Publisher Copyright: © 2022, The Author(s).
id
7c2e7e6b-b992-4fc7-9dea-d563af062c36
date added to LUP
2022-12-21 13:41:34
date last changed
2024-04-18 18:57:54
@article{7c2e7e6b-b992-4fc7-9dea-d563af062c36,
  abstract     = {{<p>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 Δ<sup>9</sup>-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.</p>}},
  author       = {{Zhang, Liying and Simonsen, Charlotte and Zimova, Lucie and Wang, Kaituo and Moparthi, Lavanya and Gaudet, Rachelle and Ekoff, Maria and Nilsson, Gunnar and Hellmich, Ute A. and Vlachova, Viktorie and Gourdon, Pontus and Zygmunt, Peter M.}},
  issn         = {{2041-1723}},
  language     = {{eng}},
  month        = {{12}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{Cannabinoid non-cannabidiol site modulation of TRPV2 structure and function}},
  url          = {{http://dx.doi.org/10.1038/s41467-022-35163-y}},
  doi          = {{10.1038/s41467-022-35163-y}},
  volume       = {{13}},
  year         = {{2022}},
}