Evidence for a GPR18 Role in Diurnal Regulation of Intraocular Pressure.
Evidence for a GPR18 Role in Diurnal Regulation of Intraocular Pressure.
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DOI：
10.1167/iovs.16-19437
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发表时间：
2016-11-01
影响因子：
4.4
通讯作者：
Straiker A
中科院分区：
文献类型：
--
作者：
Miller S;Leishman E;Oehler O;Daily L;Murataeva N;Wager-Miller J;Bradshaw H;Straiker A
一个多世纪前，人类首次描述了眼压 (IOP) 的昼夜循环。这种循环在其他物种中也得到保留。尽管大多数形式的青光眼（失明的常见原因）都表明眼压升高，但这种昼夜眼压变化的生理基础仍然是个谜。一旦确定，昼夜变化背后的系统将成为治疗干预的自然目标。使用血压正常的小鼠，我们测量了脂肪酸酰胺水解酶 (FAAH) 和 N-花生四烯酰磷脂酰乙醇胺磷脂酶 (NAPE-PLD) 对眼部脂质的调节、这些酶的 mRNA 表达及其在眼压昼夜调节中的功能作用。我们现在报告 NAPE-PLD 和 FAAH 小鼠不表现出 IOP 的昼夜循环。这些酶产生并分解酰基乙醇胺，包括内源性大麻素 anandamide。小鼠的昼夜血脂谱显示，大多数 N-酰基乙醇胺以及有趣的是 N-花生四烯酰甘氨酸 (NAGly) 的水平在夜间下降：NAGly 是花生四烯酰乙醇胺的代谢产物，也是 GPR18 的有效激动剂，可降低眼内压。 GPR18 阻断剂 O1918 在白天压力较低时会提高 IOP，但在夜间则不会。定量 PCR 分析显示，FAAH mRNA 水平随压力升高，表明 FAAH 介导了压力的变化。我们的结果支持 FAAH 依赖性 NAGly 对 GPR18 的作用作为小鼠眼压昼夜变化的生理基础。
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.
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影响因子：
2.9
作者：
Han, Bingnan;Wright, Rachel;Barker, Eric
通讯作者：
Barker, Eric
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McHugh D;Hu SS;Rimmerman N;Juknat A;Vogel Z;Walker JM;Bradshaw HB
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Bradshaw HB
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作者：
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通讯作者：
Cravatt, BF
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通讯作者：
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影响因子：
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作者：
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通讯作者：
ABUSHAAR, M