GPR119 is a G protein-coupled receptor whose stimulation increases insulin secretion. GPR119 agonists are currently in phase II clinical trails as novel therapeutics for treating type II diabetes. However, the role of GPR119 has not been examined in the eye. In preliminary studies we have found that GPR119 and candidate endogenous ligands oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) are all present in the anterior eye of the mouse. Notably, GPR119 is expressed prominently in the trabecular meshwork, responsible for outflow of aqueous humor. Preliminary functional experiments show that OEA reduces intraocular pressure (IOP) by 30% in the mouse. Elevated IOP is associated with most forms of glaucoma, a major cause of blindness worldwide. Our results suggest that a GPR119-based signaling system is present in the anterior eye and that GPR119 regulates intraocular pressure. The proposal will test this hypothesis as three specific aims. 1) Where are GPR119 receptors expressed in the murine eye? We will determine the expression pattern of GPR119 using immunocytochemistry in frozen sections of mouse eye, with GPR119 knockout controls. We will separately evaluate GPR119 mRNA expression using RT-PCR. 2) Are the putative endogenous GPR119 ligands present in the murine anterior eye? Using LC-MS we will determine the levels and diurnal variation of PEA and OEA in the anterior eye of the mouse. 3) Does GPR119 activation reduce intraocular pressure in a mouse model? Using the Tonolab measurement system we will extend preliminary experiments by testing OEA, PEA, and the potent synthetic agonist AR231453, with GPR119 knockout animals as controls. We will also test the interaction of GPR119-mediated reduction of IOP with beta-adrenergic-, alpha-adrenergic- and prostaglandin-based IOP- lowering treatments. Preliminary results suggest that GPR119 may be an entirely new means of reducing IOP, with considerable implications for glaucoma and therefore of great therapeutic potential.
Our preliminary results provide strong evidence for a GPR119-based signaling system in the mammalian eye, with receptors, ligands and function in the form of a 30% reduction in intraocular pressure. Elevated intraocular pressure is implicated in glaucoma, which causes impaired vision in millions of people around the world. The identification of a novel pathway to lower intraocular pressure is therefore of great therapeutic interest. !
|Miller, Sally; Leishman, Emma; Hu, Sherry Shujung et al. (2016) Harnessing the Endocannabinoid 2-Arachidonoylglycerol to Lower Intraocular Pressure in a Murine Model. Invest Ophthalmol Vis Sci 57:3287-96|
|Murataeva, Natalia; Li, Shimin; Oehler, Olivia et al. (2015) Cannabinoid-induced chemotaxis in bovine corneal epithelial cells. Invest Ophthalmol Vis Sci 56:3304-13|
|Smith, Tricia H; Blume, Lawrence C; Straiker, Alex et al. (2015) Cannabinoid receptor-interacting protein 1a modulates CB1 receptor signaling and regulation. Mol Pharmacol 87:747-65|
|Caldwell, Meggie D; Hu, Sherry Shu-Jung; Viswanathan, Suresh et al. (2013) A GPR18-based signalling system regulates IOP in murine eye. Br J Pharmacol 169:834-43|
|Straiker, Alex; Min, Kyung-Tai; Mackie, Ken (2013) Fmr1 deletion enhances and ultimately desensitizes CB(1) signaling in autaptic hippocampal neurons. Neurobiol Dis 56:1-5|
|Jain, Tarun; Wager-Miller, Jim; Mackie, Ken et al. (2013) Diacylglycerol lipaseÎ± (DAGLÎ±) and DAGLÎ² cooperatively regulate the production of 2-arachidonoyl glycerol in autaptic hippocampal neurons. Mol Pharmacol 84:296-302|
|Murataeva, N; Mackie, K; Straiker, A (2012) The CB2-preferring agonist JWH015 also potently and efficaciously activates CB1 in autaptic hippocampal neurons. Pharmacol Res 66:437-42|
|Hudson, Brian D; Beazley, Meggie; Szczesniak, Anna-Maria et al. (2011) Indirect sympatholytic actions at Î²-adrenoceptors account for the ocular hypotensive actions of cannabinoid receptor agonists. J Pharmacol Exp Ther 339:757-67|