title: Evidence for a GPR18 Role in Diurnal Regulation of Intraocular Pressure.
abstract: The diurnal cycling of intraocular pressure (IOP) was first described in humans more than a century ago. This cycling is preserved in other species. The physiologic underpinning of this diurnal variation in IOP remains a mystery, even though elevated pressure is indicated in most forms of glaucoma, a common cause of blindness. Once identified, the system that underlies diurnal variation would represent a natural target for therapeutic intervention.
  
  
  
  Using normotensive mice, we measured the regulation of ocular lipid species by the enzymes fatty acid amide hydrolase (FAAH) and N-arachidonoyl phosphatidylethanolamine phospholipase (NAPE-PLD), mRNA expression of these enzymes, and their functional role in diurnal regulation of IOP.
  
  
  
  We now report that NAPE-PLD and FAAH mice do not exhibit a diurnal cycling of IOP. These enzymes produce and break down acylethanolamines, including the endogenous cannabinoid anandamide. The diurnal lipid profile in mice shows that levels of most N-acyl ethanolamines and, intriguingly, N-arachidonoyl glycine (NAGly), decline at night: NAGly is a metabolite of arachidonoyl ethanolamine and a potent agonist at GPR18 that lowers intraocular pressure. The GPR18 blocker O1918 raises IOP during the day when pressure is low, but not at night. Quantitative PCR analysis shows that FAAH mRNA levels rise with pressure, suggesting that FAAH mediates the changes in pressure.
  
  
  
  Our results support FAAH-dependent NAGly action at GPR18 as the physiologic basis of the diurnal variation of intraocular pressure in mice.
authors.affiliation: The Gill Center for Biomolecular Science and the Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana, United States.
authors.forename: Sally
authors.initials: S
authors.lastname: Miller
authors.affiliation: The Gill Center for Biomolecular Science and the Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana, United States.
authors.forename: Emma
authors.initials: E
authors.lastname: Leishman
authors.affiliation: The Gill Center for Biomolecular Science and the Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana, United States.
authors.forename: Olivia
authors.initials: O
authors.lastname: Oehler
authors.affiliation: The Gill Center for Biomolecular Science and the Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana, United States.
authors.forename: Laura
authors.initials: L
authors.lastname: Daily
authors.affiliation: The Gill Center for Biomolecular Science and the Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana, United States.
authors.forename: Natalia
authors.initials: N
authors.lastname: Murataeva
authors.affiliation: The Gill Center for Biomolecular Science and the Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana, United States.
authors.forename: Jim
authors.initials: J
authors.lastname: Wager-Miller
authors.affiliation: The Gill Center for Biomolecular Science and the Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana, United States.
authors.forename: Heather
authors.initials: H
authors.lastname: Bradshaw
authors.affiliation: The Gill Center for Biomolecular Science and the Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana, United States.
authors.forename: Alex
authors.initials: A
authors.lastname: Straiker
mesh_terms: D000581:Amidohydrolases / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D002940:Circadian Rhythm / Q000502:physiology*; D005786:Gene Expression Regulation; D007429:Intraocular Pressure / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D010739:Phospholipase D / Q000096:biosynthesis / Q000235:genetics; D016133:Polymerase Chain Reaction; D012313:RNA / Q000235:genetics*; D043562:Receptors, G-Protein-Coupled / Q000096:biosynthesis / Q000235:genetics*; D053719:Tandem Mass Spectrometry; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D010739:Phospholipase D; D012313:RNA; D043562:Receptors, G-Protein-Coupled; D000099252:Fatty Acid Amide Hydrolases; C571204:GPR18 protein, mouse; C506062:Napepld protein, mouse