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Cannabinoid non-cannabidiol site modulation of TRPV2 structure and function
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(9)-tetrahydrocannabiorcol (C16) and by probe...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9722916/ https://www.ncbi.nlm.nih.gov/pubmed/36470868 http://dx.doi.org/10.1038/s41467-022-35163-y |
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author | Zhang, Liying Simonsen, Charlotte Zimova, Lucie Wang, Kaituo Moparthi, Lavanya Gaudet, Rachelle Ekoff, Maria Nilsson, Gunnar Hellmich, Ute A. Vlachova, Viktorie Gourdon, Pontus Zygmunt, Peter M. |
author_facet | Zhang, Liying Simonsen, Charlotte Zimova, Lucie Wang, Kaituo Moparthi, Lavanya Gaudet, Rachelle Ekoff, Maria Nilsson, Gunnar Hellmich, Ute A. Vlachova, Viktorie Gourdon, Pontus Zygmunt, Peter M. |
author_sort | Zhang, Liying |
collection | PubMed |
description | 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(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. |
format | Online Article Text |
id | pubmed-9722916 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-97229162022-12-07 Cannabinoid non-cannabidiol site modulation of TRPV2 structure and function Zhang, Liying Simonsen, Charlotte Zimova, Lucie Wang, Kaituo Moparthi, Lavanya Gaudet, Rachelle Ekoff, Maria Nilsson, Gunnar Hellmich, Ute A. Vlachova, Viktorie Gourdon, Pontus Zygmunt, Peter M. Nat Commun Article 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(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. Nature Publishing Group UK 2022-12-05 /pmc/articles/PMC9722916/ /pubmed/36470868 http://dx.doi.org/10.1038/s41467-022-35163-y Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Zhang, Liying Simonsen, Charlotte Zimova, Lucie Wang, Kaituo Moparthi, Lavanya Gaudet, Rachelle Ekoff, Maria Nilsson, Gunnar Hellmich, Ute A. Vlachova, Viktorie Gourdon, Pontus Zygmunt, Peter M. Cannabinoid non-cannabidiol site modulation of TRPV2 structure and function |
title | Cannabinoid non-cannabidiol site modulation of TRPV2 structure and function |
title_full | Cannabinoid non-cannabidiol site modulation of TRPV2 structure and function |
title_fullStr | Cannabinoid non-cannabidiol site modulation of TRPV2 structure and function |
title_full_unstemmed | Cannabinoid non-cannabidiol site modulation of TRPV2 structure and function |
title_short | Cannabinoid non-cannabidiol site modulation of TRPV2 structure and function |
title_sort | cannabinoid non-cannabidiol site modulation of trpv2 structure and function |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9722916/ https://www.ncbi.nlm.nih.gov/pubmed/36470868 http://dx.doi.org/10.1038/s41467-022-35163-y |
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