N-arachidonoyl glycine, another endogenous agonist of GPR55

Console-Bram, Linda; Ciuciu, Sandra M.; Zhao, Pingwei; Zipkin, Robert E.; Brǎiloiu, Eugen; Abood, Mary E.

doi:10.1016/j.bbrc.2017.07.038

Cited by 21 publications

(17 citation statements)

References 24 publications

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“…One key issue when addressing the question of the cellular effects of NAGly is to determine whether it interferes directly with the activity of its targets or recruits dedicated G-protein coupled receptors (GPCRs) linked to downstream intracellular signaling cascades. NAGly has been proposed to act as an agonist of some orphan GPCRs like GPR18 10 , GPR55 11 , and GPR92 12 . It is however worthy of note that NAGly can influence the activity of some effectors without the requirement of GPCRs.…”

mentioning

confidence: 99%

Inhibition of store-operated calcium channels by N-arachidonoyl glycine (NAGly): no evidence for the involvement of lipid-sensing G protein coupled receptors

Deveci

Hasna

Bouron

2020

Sci Rep

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n-arachidonoyl glycine (nAGly) is an endogenous lipid deriving from the endocannabinoid anandamide (AEA). Identified as a ligand of several G-protein coupled receptors (GPCRs), it can however exert biological responses independently of GPCRs. NAGly was recently shown to depress store-operated ca 2+ entry (SOCE) but its mechanism of action remains elusive. The major aim of this study was to gain a better knowledge on the NAGly-dependent impairment of SOCE in neurons of the central nervous system (CNS) from mice. First, we examined the expression of genes encoding for putative lipid sensing GPCRs using transcriptomic data publicly available. This analysis showed that the most abundant GPCRs transcripts present in the cerebral cortices of embryonic brains were coding for lysophosphatidic acid (LPA) and sphingosine-1 phosphate (S1P) receptors. Next, the presence of functional receptors was assessed with live-cell calcium imaging experiments. In primary cortical cells S1P and LPA mobilize ca 2+ from internal stores via a mechanism sensitive to the S1P and LPA receptor antagonists Ex26, H2L5186303, or Ki16425. However, none of these compounds prevented or attenuated the NAGlydependent impairment of Soce. We found no evidence for the requirement of lipid sensing GpcRs in this inhibitory process, indicating that NAGly is an endogenous modulator interfering with the core machinery of Soce. Moreover, these data also raise the intriguing possibility that the depression of SOCE could play a role in the central effects of NAGly.

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confidence: 99%

Inhibition of store-operated calcium channels by N-arachidonoyl glycine (NAGly): no evidence for the involvement of lipid-sensing G protein coupled receptors

Deveci

Hasna

Bouron

2020

Sci Rep

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“…Different G-protein coupled receptors (GPCRs) account for NAraGly biological functions (see Table 1) and FAAH and COX-2 might affect its endogenous levels and bioactivity. Among GPCRs, NAraGly shows high affinity for the orphan GPR18 [31], GPR55 [32] and GPR92 [33], whereas it does not bind to CB 1 [6] or CB 2 [31]. Although GPR18 binding assays have not been validated yet, several pieces of evidence supported the involvement of GPR18 in mediating some physiological and functional activities of NAraGly including calcium mobilization [31], control of cell apoptosis [34] and migration [35], anti-inflammatory action [36], neuropathic pain [37], diurnal regulation of intraocular pressure [38] and microglial-neuronal communication [39].…”

Section: N-acyl Glycinesmentioning

confidence: 99%

“…However, the role of NAraGly as GPR18 agonist is still debated, since controversial results were obtained by screening NAraGly in the β-arrestin PathHunter™ system [41] as well as in a native neuronal system [42]. Recently, Console-Bram and co-workers, by using a stable cell line expressing hemagglutinin (HA) incorporated into the N-terminus of the human GPR55 cDNA (HAGPR55/CHO), reported that NAraGly behaved as GPR55 agonist [32]. Indeed, NAraGly in a dose-dependent manner increased intracellular calcium levels and mitogen-activated protein kinase (MAPK) signaling, and these effects were selectively blocked by specific GPR55 antagonist [32].…”

Section: N-acyl Glycinesmentioning

confidence: 99%

“…Recently, Console-Bram and co-workers, by using a stable cell line expressing hemagglutinin (HA) incorporated into the N-terminus of the human GPR55 cDNA (HAGPR55/CHO), reported that NAraGly behaved as GPR55 agonist [32]. Indeed, NAraGly in a dose-dependent manner increased intracellular calcium levels and mitogen-activated protein kinase (MAPK) signaling, and these effects were selectively blocked by specific GPR55 antagonist [32]. Finally, molecular modeling and site-directed mutagenesis studies revealed specific amino acidic residues required to GPR92 to bind to both hydrocarbon chain and glycine moiety of NAraGly [33].…”

Section: N-acyl Glycinesmentioning

confidence: 99%

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N-Acyl Amino Acids: Metabolism, Molecular Targets, and Role in Biological Processes

2019

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The lipid signal is becoming increasingly crowded as increasingly fatty acid amide derivatives are being identified and considered relevant therapeutic targets. The identification of N-arachidonoyl-ethanolamine as endogenous ligand of cannabinoid type-1 and type-2 receptors as well as the development of different–omics technologies have the merit to have led to the discovery of a huge number of naturally occurring N-acyl-amines. Among those mediators, N-acyl amino acids, chemically related to the endocannabinoids and belonging to the complex lipid signaling system now known as endocannabinoidome, have been rapidly growing for their therapeutic potential. Here, we review the current knowledge of the mechanisms for the biosynthesis and inactivation of the N-acyl amino acids, as well as the various molecular targets for some of the N-acyl amino acids described so far.

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“…Treatment of mice with CID16020046 counteracted the anxiogenic and other behavioural effects of the cannabinoid ligand LH-21, which had previously been suggested to act via GPR55 and independently of cannabinoid CB 1 receptor [26]. Antagonists have also been used to confirm affinity for GPR55 of newly recognised lipid agonists, including LPC (lysophosphaditylcholine) and N-arachidonoylglycine [27][28][29]. Finally, evidence is emerging that GPR55 antagonists could be clinically efficacious in neurological disease.…”

Section: Introductionmentioning

confidence: 99%

Structure-Activity Relationship of the GPR55 Antagonist, CID16020046

Brown¹,

Castellano-Pellicena²,

Haslam³

et al. 2018

Pharmacology

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Background/Aims: CID16020046 blocks the effect of the lipid lysophosphatidylinositol (LPI) at its receptor, GPR55. CID16020046 and another antagonist, ML193, have been used to investigate GPR55-mediated effects of LPI on cells, tissues, and in vivo. Here we describe the structure-activity relationship of CID16020046. Methods: Yeast or human cells were engineered to express GPR55 or control receptors. Cells were pretreated with a test agent before agonist challenge. Functional responses were quantified by yeast gene-reporter or calcium imaging. Results: Three substituents around the central pyrazololactam core of CID16020046 are each tolerant to substitution without abolishing GPR55 activity. Analogues of CID16020046 with potency at GPR55 ranging >1,000-fold are described, including several lacking activity up to the top concentration tested. One analogue, compound 1 (GSK875734A), has approximately 50-fold greater potency than CID16020046 in an inverse agonist assay. CID16020046, ML193 and 2 further antagonists (ML191 and ML192) all block the effect of a surrogate agonist at human GPR55. ML193, CID16020046 and several other examples of the pyrazololactam chemotype were also shown to antagonise rat GPR55. Conclusion: These data confirm the utility of CID16020046 and ML193 as tools to investigate the physiological role of GPR55, and offer starting points for GPR55 antagonists with optimised pharmacokinetic or other properties.

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N-arachidonoyl glycine, another endogenous agonist of GPR55

Cited by 21 publications

References 24 publications

Inhibition of store-operated calcium channels by N-arachidonoyl glycine (NAGly): no evidence for the involvement of lipid-sensing G protein coupled receptors

Inhibition of store-operated calcium channels by N-arachidonoyl glycine (NAGly): no evidence for the involvement of lipid-sensing G protein coupled receptors

N-Acyl Amino Acids: Metabolism, Molecular Targets, and Role in Biological Processes

Structure-Activity Relationship of the GPR55 Antagonist, CID16020046

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