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Endogenous unsaturated C18 N-acylethanolamines are vanilloid receptor (TRPV1) agonists.

Movahed Rad, Pouya LU ; Jönsson, Bo A LU ; Birnir, Bryndis LU ; Wingstrand, Johan LU ; Dyhring Jørgensen, Tino ; Ermund, Anna LU ; Sterner, Olov LU ; Zygmunt, Peter LU orcid and Högestätt, Edward LU (2005) In Journal of Biological Chemistry 280(46). p.38496-38504
Abstract
The endogenous C18 N-acylethanolamines (NAEs) N-linolenoylethanolamine (18:3 NAE), N-linoleoylethanolamine (18:2 NAE), N-oleoylethanolamine (18:1 NAE), and N-stearoylethanolamine (18:0 NAE) are structurally related to the endocannabinoid anandamide (20:4 NAE), but these lipids are poor ligands at cannabinoid CB1 receptors. Anandamide is also an activator of the transient receptor potential (TRP) vanilloid 1 (TRPV1) on primary sensory neurons. Here we show that C18 NAEs are present in rat sensory ganglia and vascular tissue. With the exception of 18:3 NAE in rat sensory ganglia, the levels of C18 NAEs are equal to or substantially exceed those of anandamide. At submicromolar concentrations, 18:3 NAE, 18:2 NAE, and 18:1 NAE, but not 18:0 NAE... (More)
The endogenous C18 N-acylethanolamines (NAEs) N-linolenoylethanolamine (18:3 NAE), N-linoleoylethanolamine (18:2 NAE), N-oleoylethanolamine (18:1 NAE), and N-stearoylethanolamine (18:0 NAE) are structurally related to the endocannabinoid anandamide (20:4 NAE), but these lipids are poor ligands at cannabinoid CB1 receptors. Anandamide is also an activator of the transient receptor potential (TRP) vanilloid 1 (TRPV1) on primary sensory neurons. Here we show that C18 NAEs are present in rat sensory ganglia and vascular tissue. With the exception of 18:3 NAE in rat sensory ganglia, the levels of C18 NAEs are equal to or substantially exceed those of anandamide. At submicromolar concentrations, 18:3 NAE, 18:2 NAE, and 18:1 NAE, but not 18:0 NAE and oleic acid, activate native rTRPV1 on perivascular sensory nerves. 18:1 NAE does not activate these nerves in TRPV1 gene knock-out mice. Only the unsaturated C18 NAEs elicit whole cell currents and fluorometric calcium responses in HEK293 cells expressing hTRPV1. Molecular modeling revealed a low energy cluster of U-shaped unsaturated NAE conformers, sharing several pharmacophoric elements with capsaicin. Furthermore, one of the two major low energy conformational families of anandamide also overlaps with the cannabinoid CB1 receptor ligand HU210, which is in line with anandamide being a dual activator of TRPV1 and the cannabinoid CB1 receptor. This study shows that several endogenous non-cannabinoid NAEs, many of which are more abundant than anandamide in rat tissues, activate TRPV1 and thus may play a role as endogenous TRPV1 modulators. (Less)
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type
Contribution to journal
publication status
published
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in
Journal of Biological Chemistry
volume
280
issue
46
pages
38496 - 38504
publisher
American Society for Biochemistry and Molecular Biology
external identifiers
  • wos:000233239800047
  • scopus:33644682883
ISSN
1083-351X
DOI
10.1074/jbc.M507429200
language
English
LU publication?
yes
additional info
The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Division of Clinical Chemistry and Pharmacology (013250300), Department of Experimental Medical Science (013210000), Division of Occupational and Environmental Medicine (013078001), Organic chemistry (S/LTH) (011001240), Faculty of Medicine (000022000)
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65b8abac-1570-49c1-b332-17314f1a7ea5 (old id 142957)
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http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=16081411&dopt=Abstract
date added to LUP
2016-04-01 11:42:59
date last changed
2021-10-06 01:16:31
@article{65b8abac-1570-49c1-b332-17314f1a7ea5,
  abstract     = {The endogenous C18 N-acylethanolamines (NAEs) N-linolenoylethanolamine (18:3 NAE), N-linoleoylethanolamine (18:2 NAE), N-oleoylethanolamine (18:1 NAE), and N-stearoylethanolamine (18:0 NAE) are structurally related to the endocannabinoid anandamide (20:4 NAE), but these lipids are poor ligands at cannabinoid CB1 receptors. Anandamide is also an activator of the transient receptor potential (TRP) vanilloid 1 (TRPV1) on primary sensory neurons. Here we show that C18 NAEs are present in rat sensory ganglia and vascular tissue. With the exception of 18:3 NAE in rat sensory ganglia, the levels of C18 NAEs are equal to or substantially exceed those of anandamide. At submicromolar concentrations, 18:3 NAE, 18:2 NAE, and 18:1 NAE, but not 18:0 NAE and oleic acid, activate native rTRPV1 on perivascular sensory nerves. 18:1 NAE does not activate these nerves in TRPV1 gene knock-out mice. Only the unsaturated C18 NAEs elicit whole cell currents and fluorometric calcium responses in HEK293 cells expressing hTRPV1. Molecular modeling revealed a low energy cluster of U-shaped unsaturated NAE conformers, sharing several pharmacophoric elements with capsaicin. Furthermore, one of the two major low energy conformational families of anandamide also overlaps with the cannabinoid CB1 receptor ligand HU210, which is in line with anandamide being a dual activator of TRPV1 and the cannabinoid CB1 receptor. This study shows that several endogenous non-cannabinoid NAEs, many of which are more abundant than anandamide in rat tissues, activate TRPV1 and thus may play a role as endogenous TRPV1 modulators.},
  author       = {Movahed Rad, Pouya and Jönsson, Bo A and Birnir, Bryndis and Wingstrand, Johan and Dyhring Jørgensen, Tino and Ermund, Anna and Sterner, Olov and Zygmunt, Peter and Högestätt, Edward},
  issn         = {1083-351X},
  language     = {eng},
  number       = {46},
  pages        = {38496--38504},
  publisher    = {American Society for Biochemistry and Molecular Biology},
  series       = {Journal of Biological Chemistry},
  title        = {Endogenous unsaturated C18 N-acylethanolamines are vanilloid receptor (TRPV1) agonists.},
  url          = {http://dx.doi.org/10.1074/jbc.M507429200},
  doi          = {10.1074/jbc.M507429200},
  volume       = {280},
  year         = {2005},
}