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Alex Straiker, olivia oehler, Laura Daily, emma leishman, Heather Bradshaw; Evidence for GPR18 role in diurnal regulation of intraocular pressure. Invest. Ophthalmol. Vis. Sci. 2016;57(12):3038.
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It has been known for over a century that intraocular pressure (IOP) cycles diurnally, rising during the day and declining at night. This diurnal variation is preserved in other vertebrates, though in some species such as mouse the cycle is reversed. The physiological underpinning of this diurnal variation in IOP remains a mystery; this even though elevated pressure is indicated in most forms of glaucoma, a common form of blindness. Once identified, the system that underlies diurnal variation would represent a natural target for therapeutic intervention.
Using normotensive mice, we have explored the regulation of ocular lipid species by the enzymes fatty acid amide hydrolase (FAAH) and N-arachidonoyl phosphatidylethanolamine phospholipase (NAPE-PLD) as well as their functional role in diurnal regulation of IOP.
We have previously reported that CB1, CB2, and GPR55 knockout mice retain diurnal variation in IOP but now report that NAPE-PLD and FAAH mice do not. These enzymes produce and break down acylethanolamines, including endogenous cannabinoids and their congeners. Consistent with this the diurnal lipid profile shows that levels of most acylethanolamines and, intriguingly, N-arachidonoyl glycine (NAGly), rise at night in mice. NAGly is a metabolite of arachidonoyl ethanolamide and a potent agonist at GPR18 that we have shown to lower intraocular pressure. The GPR18 blocker O1918 raises IOP during the day when pressure is low, but not at night.
Our results support NAGly action at GPR18 as the physiological basis of the diurnal variation of intraocular pressure in mice
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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