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Cannabinoid non-cannabidiol site modulation of TRPV2 structure and function

Author

Listed:
  • Liying Zhang

    (Lund University
    Lund University
    University of Copenhagen)

  • Charlotte Simonsen

    (Lund University)

  • Lucie Zimova

    (Czech Academy of Sciences)

  • Kaituo Wang

    (University of Copenhagen)

  • Lavanya Moparthi

    (Linköping University
    Linköping University)

  • Rachelle Gaudet

    (Harvard University)

  • Maria Ekoff

    (Karolinska University Hospital)

  • Gunnar Nilsson

    (Karolinska University Hospital)

  • Ute A. Hellmich

    (Friedrich Schiller University Jena
    Goethe-University)

  • Viktorie Vlachova

    (Czech Academy of Sciences)

  • Pontus Gourdon

    (Lund University
    University of Copenhagen)

  • Peter M. Zygmunt

    (Lund University)

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.

Suggested Citation

  • Liying Zhang & Charlotte Simonsen & Lucie Zimova & Kaituo Wang & Lavanya Moparthi & Rachelle Gaudet & Maria Ekoff & Gunnar Nilsson & Ute A. Hellmich & Viktorie Vlachova & Pontus Gourdon & Peter M. Zyg, 2022. "Cannabinoid non-cannabidiol site modulation of TRPV2 structure and function," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-35163-y
    DOI: 10.1038/s41467-022-35163-y
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    References listed on IDEAS

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    1. Yuan Gao & Erhu Cao & David Julius & Yifan Cheng, 2016. "TRPV1 structures in nanodiscs reveal mechanisms of ligand and lipid action," Nature, Nature, vol. 534(7607), pages 347-351, June.
    2. Michael J. Caterina & Mark A. Schumacher & Makoto Tominaga & Tobias A. Rosen & Jon D. Levine & David Julius, 1997. "The capsaicin receptor: a heat-activated ion channel in the pain pathway," Nature, Nature, vol. 389(6653), pages 816-824, October.
    3. David A Andersson & Clive Gentry & Lisa Alenmyr & Dan Killander & Simon E Lewis & Anders Andersson & Bernard Bucher & Jean-Luc Galzi & Olov Sterner & Stuart Bevan & Edward D Högestätt & Peter M Zygmun, 2011. "TRPA1 mediates spinal antinociception induced by acetaminophen and the cannabinoid Δ9-tetrahydrocannabiorcol," Nature Communications, Nature, vol. 2(1), pages 1-11, September.
    4. Kevin W. Huynh & Matthew R. Cohen & Jiansen Jiang & Amrita Samanta & David T. Lodowski & Z. Hong Zhou & Vera Y. Moiseenkova-Bell, 2016. "Structure of the full-length TRPV2 channel by cryo-EM," Nature Communications, Nature, vol. 7(1), pages 1-8, September.
    5. Ruth A. Pumroy & Anna D. Protopopova & Tabea C. Fricke & Iris U. Lange & Ferdinand M. Haug & Phuong T. Nguyen & Pamela N. Gallo & Bárbara B. Sousa & Gonçalo J. L. Bernardes & Vladimir Yarov-Yarovoy & , 2022. "Structural insights into TRPV2 activation by small molecules," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    6. Kirill D. Nadezhdin & Arthur Neuberger & Yury A. Nikolaev & Lyle A. Murphy & Elena O. Gracheva & Sviatoslav N. Bagriantsev & Alexander I. Sobolevsky, 2021. "Extracellular cap domain is an essential component of the TRPV1 gating mechanism," Nature Communications, Nature, vol. 12(1), pages 1-8, December.
    7. Michael J. Caterina & Tobias A. Rosen & Makoto Tominaga & Anthony J. Brake & David Julius, 1999. "A capsaicin-receptor homologue with a high threshold for noxious heat," Nature, Nature, vol. 398(6726), pages 436-441, April.
    8. Sven-Eric Jordt & Diana M. Bautista & Huai-hu Chuang & David D. McKemy & Peter M. Zygmunt & Edward D. Högestätt & Ian D. Meng & David Julius, 2004. "Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1," Nature, Nature, vol. 427(6971), pages 260-265, January.
    9. Arthur Neuberger & Kirill D. Nadezhdin & Alexander I. Sobolevsky, 2021. "Structural mechanisms of TRPV6 inhibition by ruthenium red and econazole," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
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