title: A GPR18-based signalling system regulates IOP in murine eye.
abstract: OBJECTIVE
  GPR18 is a recently deorphaned lipid receptor that is activated by the endogenous lipid N-arachidonoyl glycine (NAGly) as well the behaviourally inactive atypical cannabinoid, abnormal cannabidiol (Abn-CBD). The presence and/or function of any GPR18-based ocular signalling system remain essentially unstudied. The objectives of this research are: (i) to determine the disposition of GPR18 receptors and ligands in anterior murine eye, (ii) examine the effect of GPR18 activation on intraocular pressure (IOP) in a murine model, including knockout mice for CB₁, CB₂ and GPR55.
  
  
  METHODS
  IOP was measured in mice following topical application of Abn-CBD, NAGly or the GPR55/GPR18 agonist O-1602, alone or with injection of the GPR18 antagonist, O-1918. GPR18 protein localization was assessed with immunohistochemistry. Endocannabinoids were measured using LC/MS-MS.
  
  
  RESULTS
  GPR18 protein was expressed most prominently in the ciliary epithelium and the corneal epithelium and, interestingly, in the trabecular meshwork. The GPR18 ligand, NAGly, was also detected in mouse eye at a level comparable to that seen in the brain. Abn-CBD and NAGly, but not O-1602, significantly reduced IOP in all mice tested. The antagonist, O-1918, blocked the effects of Abn-CBD and NAGly.
  
  
  CONCLUSIONS
  We present evidence for a functional GPR18-based signalling system in the murine anterior eye, including receptors and ligands. GPR18 agonists, Abn-CBD and NAGly, reduce IOP independently of CB₁, CB₂ or GPR55. These findings suggest that GPR18 may serve as a desirable target for the development of novel ocular hypotensive medications.
authors: Department of Clinical Vision Science, Dalhousie University, Halifax, NS, Canada.
authors: Meggie D
authors: MD
authors: Caldwell
authors: Sherry Shu-Jung
authors: SS
authors: Hu
authors: Suresh
authors: S
authors: Viswanathan
authors: Heather
authors: H
authors: Bradshaw
authors: Melanie E M
authors: ME
authors: Kelly
authors: Alex
authors: A
authors: Straiker
mesh_terms: D060433:Administration, Ophthalmic; D000818:Animals; D000869:Anterior Eye Segment / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D001095:Arachidonic Acids / Q000008:administration & dosage / Q000378:metabolism; D063386:Cannabinoid Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology; D063387:Cannabinoid Receptor Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D002924:Ciliary Body / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D063388:Endocannabinoids / Q000378:metabolism; D019573:Epithelium, Corneal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005136:Eye Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005998:Glycine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000378:metabolism; D007429:Intraocular Pressure / Q000187:drug effects; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000235:genetics / Q000378:metabolism; D043882:Receptors, Cannabinoid / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012118:Resorcinols / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C479832:4-(3-3,4-p-menthadien-(1,8)-yl)olivetol; D001095:Arachidonic Acids; C578453:CNR1 protein, mouse; D063386:Cannabinoid Receptor Agonists; D063387:Cannabinoid Receptor Antagonists; C571431:Cnr2 protein, mouse; D063388:Endocannabinoids; D005136:Eye Proteins; C571204:GPR18 protein, mouse; C526692:GPR55 protein, mouse; D008024:Ligands; C465623:N-arachidonylglycine; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D043882:Receptors, Cannabinoid; D043562:Receptors, G-Protein-Coupled; D012118:Resorcinols; D005998:Glycine