Orphan endogenous lipids and orphan GPCRs: A good match

Bradshaw, Heather B.; Lee, Sung Ha; McHugh, Douglas

doi:10.1016/j.prostaglandins.2009.04.006

Cited by 39 publications

(31 citation statements)

References 43 publications

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“…It is possible that some of the remaining lipids in this panel for which there is currently no known role will be found to partner with orphan GPCRs or other receptors. 43 It is difficult to interpret the remaining changes in lipid levels seen in WT, NAPE-PLD, and FAAH knockout mice. Although statistically significant, some of these may be secondary or even tertiary effects as levels of precursors for other lipids are skewed in a dynamic system.…”

Section: Discussionmentioning

confidence: 99%

Evidence for a GPR18 Role in Diurnal Regulation of Intraocular Pressure

Miller

Leishman

Oehler

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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PurposeThe 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.MethodsUsing 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.ResultsWe 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.ConclusionsOur 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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Section: Discussionmentioning

confidence: 99%

Evidence for a GPR18 Role in Diurnal Regulation of Intraocular Pressure

Miller

Leishman

Oehler

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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“…In addition to the N-acylethanolamides, more than 70 N -acylamide derivatives of amino acids and neurotransmitters have been detected in the brain [45,46]. A number of these N -acylamides have bioactivity.…”

Section: N-docosahexaenoylamide Derivativesmentioning

confidence: 99%

A synaptogenic amide N-docosahexaenoylethanolamide promotes hippocampal development

Kim

Spector

Xiong

2011

Prostaglandins & Other Lipid Mediators

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Docosahexaenoic acid (DHA), the n-3 essential fatty acid that is highly enriched in the brain, increases neurite growth and synaptogenesis in cultured mouse fetal hippocampal neurons. These cellular effects may underlie the DHA-induced enhancement of hippocampus-dependent learning and memory functions. We found that N-docsahexaenoylethanolamide (DEA), an ethanolamide derivative of DHA, is a potent mediator for these actions. This is supported by the observation that DHA is converted to DEA by fetal mouse hippocampal neuron cultures and a hippocampal homogenate, and DEA is present endogenously in the mouse hippocampus. Furthermore, DEA stimulates neurite growth and synaptogenesis at substantially lower concentrations than DHA, and it enhances glutamatergic synaptic activities with concomitant increases in synapsin and glutamate receptor subunit expression in the hippocampal neurons. These findings suggest that DEA, an ethanolamide derivative of DHA, is a synaptogenic factor, and therefore we suggest utilizing the term ‘synaptamide’. This brief review summarizes the neuronal production and actions of synaptamide and describes other N-docosahexaenoyl amides that are present in the brain.

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“…Fatty acid amide hydrolase (FAAH) is primarily responsible for the intracellular degradation of AEA into arachidonic acid (AA) and ethanol amine 12 . In addition, FAAH has been identified as the key enzyme in the metabolism of N -arachidonyl glycine as well as its family of endogenous structural analogs 13, 14 . FAAH possesses a number of channels and cavities involved in substrate or inhibitor binding and by using specific FAAH inhibitors the level of the endogenous AEA and potentially other lipids can be elevated and thus its action in the organism prolonged and intensified.…”

Section: Introductionmentioning

confidence: 99%

Experimental colitis in mice is attenuated by changes in the levels of endocannabinoid metabolites induced by selective inhibition of fatty acid amide hydrolase (FAAH)

et al. 2014

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Background and aims Pharmacological treatment and/or maintenance of remission in inflammatory bowel diseases (IBD) is currently one of the biggest challenge in the field of gastroenterology. Available therapies are mostly limited to overcoming the symptoms, but not the cause of the disease. Recently, the endocannabinoid system has been proposed as a novel target in the treatment of IBD. Here we aimed to assess the anti-inflammatory action of the novel fatty acid amide hydrolase (FAAH) inhibitor PF-3845 and its effect on the endocannabinoid and related lipid metabolism during the course of experimental colitis. Methods We used two models of experimental colitis in mice (TNBS- and DSS-induced) and additionally, we employed LC/MS/MS spectrometry to determine the changes in biolipid levels in the mouse colon during inflammation. Results We showed that the FAAH inhibitor PF-3845 reduced experimental TNBS-induced colitis in mice and its anti-inflammatory action is associated with altering the levels of selected biolipids (arachidonic and oleic acid derivatives, prostaglandins and biolipids containing glycine in the mouse colon). Conclusions We show that FAAH is a promising pharmacological target and the FAAH-dependent biolipids play a major role in colitis. Our results highlight and promote therapeutic strategy based on targeting FAAH-dependent metabolic pathways in order to alleviate intestinal inflammation.

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Orphan endogenous lipids and orphan GPCRs: A good match

Cited by 39 publications

References 43 publications

Evidence for a GPR18 Role in Diurnal Regulation of Intraocular Pressure

Evidence for a GPR18 Role in Diurnal Regulation of Intraocular Pressure

A synaptogenic amide N-docosahexaenoylethanolamide promotes hippocampal development

Experimental colitis in mice is attenuated by changes in the levels of endocannabinoid metabolites induced by selective inhibition of fatty acid amide hydrolase (FAAH)

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