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Anandamide and arachidonic acid use epoxyeicosatrienoic acids to activate TRPV4 channels

Author

Listed:
  • Hiroyuki Watanabe

    (Campus Gasthuisberg)

  • Joris Vriens

    (Campus Gasthuisberg)

  • Jean Prenen

    (Campus Gasthuisberg)

  • Guy Droogmans

    (Campus Gasthuisberg)

  • Thomas Voets

    (Campus Gasthuisberg)

  • Bernd Nilius

    (Campus Gasthuisberg)

Abstract

TRPV4 is a widely expressed cation channel of the ‘transient receptor potential’ (TRP) family1 that is related to the vanilloid receptor VR1 (TRPV1). It functions as a Ca2+ entry channel2 and displays remarkable gating promiscuity by responding to both physical stimuli (cell swelling, innoxious heat2,3,4,5,6,7) and the synthetic ligand 4αPDD8. An endogenous ligand for this channel has not yet been identified. Here we show that the endocannabinoid anandamide and its metabolite arachidonic acid activate TRPV4 in an indirect way involving the cytochrome P450 epoxygenase-dependent formation of epoxyeicosatrienoic acids. Application of 5′,6′-epoxyeicosatrienoic acid at submicromolar concentrations activates TRPV4 in a membrane-delimited manner and causes Ca2+ influx through TRPV4-like channels in vascular endothelial cells. Activation of TRPV4 in vascular endothelial cells might therefore contribute to the relaxant effects of endocannabinoids and their P450 epoxygenase-dependent metabolites on vascular tone9,10,11,12.

Suggested Citation

  • Hiroyuki Watanabe & Joris Vriens & Jean Prenen & Guy Droogmans & Thomas Voets & Bernd Nilius, 2003. "Anandamide and arachidonic acid use epoxyeicosatrienoic acids to activate TRPV4 channels," Nature, Nature, vol. 424(6947), pages 434-438, July.
    • Handle: RePEc:nat:nature:v:424:y:2003:i:6947:d:10.1038_nature01807
    DOI: 10.1038/nature01807
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    Cited by:

    1. Do Hoon Kwon & Feng Zhang & Brett A. McCray & Shasha Feng & Meha Kumar & Jeremy M. Sullivan & Wonpil Im & Charlotte J. Sumner & Seok-Yong Lee, 2023. "TRPV4-Rho GTPase complex structures reveal mechanisms of gating and disease," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    2. Kirill D. Nadezhdin & Irina A. Talyzina & Aravind Parthasarathy & Arthur Neuberger & David X. Zhang & Alexander I. Sobolevsky, 2023. "Structure of human TRPV4 in complex with GTPase RhoA," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    3. Annika Simon & Thomas Einem & Alexander Seidinger & Michaela Matthey & Laura Bindila & Daniela Wenzel, 2022. "The endocannabinoid anandamide is an airway relaxant in health and disease," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    4. Gaurav Bhardwaj & Kyung Dae Ko & Yoojin Hong & Zhenhai Zhang & Ngai Lam Ho & Sree V Chintapalli & Lindsay A Kline & Matthew Gotlin & David Nicholas Hartranft & Morgen E Patterson & Foram Dave & Evan J, 2012. "PHYRN: A Robust Method for Phylogenetic Analysis of Highly Divergent Sequences," PLOS ONE, Public Library of Science, vol. 7(4), pages 1-13, April.

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