title: Monoacylglycerols activate TRPV1--a link between phospholipase C and TRPV1.
abstract: Phospholipase C-mediated hydrolysis of phosphatidylinositol 4,5-bisphosphate generates diacylglycerol, inositol 1,4,5-trisphosphate and protons, all of which can regulate TRPV1 activity via different mechanisms. Here we explored the possibility that the diacylglycerol metabolites 2-arachidonoylglycerol and 1-arachidonoylglycerol, and not metabolites of these monoacylglycerols, activate TRPV1 and contribute to this signaling cascade. 2-Arachidonoylglycerol and 1-arachidonoylglycerol activated native TRPV1 on vascular sensory nerve fibers and heterologously expressed TRPV1 in whole cells and inside-out membrane patches. The monoacylglycerol lipase inhibitors methylarachidonoyl-fluorophosphonate and JZL184 prevented the metabolism of deuterium-labeled 2-arachidonoylglycerol and deuterium-labeled 1-arachidonoylglycerol in arterial homogenates, and enhanced TRPV1-mediated vasodilator responses to both monoacylglycerols. In mesenteric arteries from TRPV1 knock-out mice, vasodilator responses to 2-arachidonoylglycerol were minor. Bradykinin and adenosine triphosphate, ligands of phospholipase C-coupled membrane receptors, increased the content of 2-arachidonoylglycerol in dorsal root ganglia. In HEK293 cells expressing the phospholipase C-coupled histamine H1 receptor, exposure to histamine stimulated the formation of 2-AG, and this effect was augmented in the presence of JZL184. These effects were prevented by the diacylglycerol lipase inhibitor tetrahydrolipstatin. Histamine induced large whole cell currents in HEK293 cells co-expressing TRPV1 and the histamine H1 receptor, and the TRPV1 antagonist capsazepine abolished these currents. JZL184 increased the histamine-induced currents and tetrahydrolipstatin prevented this effect. The calcineurin inhibitor ciclosporin and the endogenous "entourage" compound palmitoylethanolamide potentiated the vasodilator response to 2-arachidonoylglycerol, disclosing TRPV1 activation of this monoacylglycerol at nanomolar concentrations. Furthermore, intracerebroventricular injection of JZL184 produced TRPV1-dependent antinociception in the mouse formalin test. Our results show that intact 2-arachidonoylglycerol and 1-arachidonoylglycerol are endogenous TRPV1 activators, contributing to phospholipase C-dependent TRPV1 channel activation and TRPV1-mediated antinociceptive signaling in the brain.
authors: Department of Laboratory Medicine, Lund University, Lund, Sweden ; Lund University Pain Research Centre, Lund University, Lund, Sweden.
authors: Peter M
authors: PM
authors: Zygmunt
authors: Anna
authors: A
authors: Ermund
authors: Pouya
authors: P
authors: Movahed
authors: David A
authors: DA
authors: Andersson
authors: Charlotte
authors: C
authors: Simonsen
authors: Bo A G
authors: BA
authors: Jönsson
authors: Anders
authors: A
authors: Blomgren
authors: Bryndis
authors: B
authors: Birnir
authors: Stuart
authors: S
authors: Bevan
authors: Alain
authors: A
authors: Eschalier
authors: Christophe
authors: C
authors: Mallet
authors: Ana
authors: A
authors: Gomis
authors: Edward D
authors: ED
authors: Högestätt
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000096:biosynthesis; D052117:Benzodioxoles / Q000494:pharmacology; D063388:Endocannabinoids / Q000096:biosynthesis; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005989:Glycerides / Q000096:biosynthesis; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D050178:Monoglycerides / Q000096:biosynthesis / Q000378:metabolism*; D059225:Nociception / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D011984:Sensory Receptor Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D050916:TRPV Cation Channels / Q000378:metabolism*; D010738:Type C Phospholipases / Q000378:metabolism*
chemical_list: D001095:Arachidonic Acids; D052117:Benzodioxoles; D063388:Endocannabinoids; D005989:Glycerides; C534333:JZL 184; D050178:Monoglycerides; D010880:Piperidines; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; C493921:TRPV1 protein, mouse; C493922:Trpv1 protein, rat; C094503:glyceryl 2-arachidonate; D010738:Type C Phospholipases