Activation of <scp>GPR</scp>18 by cannabinoid compounds: a tale of biased agonism

Console-Bram, Linda; Brǎiloiu, Eugen; Brailoiu, G. Cristina; Sharir, Haleli; Abood, Mary E.

doi:10.1111/bph.12746

Cited by 135 publications

(173 citation statements)

References 41 publications

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“…Nonetheless, these findings support a role for Akt phosphorylation in central GPR18 signaling. Furthermore, the current pharmacological and signal transduction findings support the concept of "biased agonism" suggested by Console-Bram et al (2014) as a reasonable explanation for reported findings that questioned GPR18 as being the Abn CBD receptor (Yin et al, 2009;Lu et al, 2013).…”

Section: Mechanisms For Central Gpr18-mediated Hypotensionsupporting

confidence: 87%

Neuronal Nitric Oxide Synthase–Dependent Elevation in Adiponectin in the Rostral Ventrolateral Medulla Underlies G Protein–Coupled Receptor 18–Mediated Hypotension in Conscious Rats

Penumarti

Abdel‐Rahman

2014

J Pharmacol Exp Ther

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Direct activation of the endocannabinoid receptor G protein-coupled receptor 18 (GPR18) in the rostral ventrolateral medulla (RVLM) of conscious rats by abnormal cannabidiol (Abn CBD; trans-4-[3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol) elevates local nitric oxide (NO) and adiponectin (ADN) levels and reduces oxidative stress and blood pressure (BP). However, the molecular mechanisms for GPR18-mediated neurochemical responses, including the nitric oxide synthase isoform that generates NO, and their potential causal link to the BP reduction are not known. We hypothesized that GPR18-mediated enhancement of Akt, extracellular signal-regulated kinase 1/2 (ERK1/2), and neuronal nitric oxide synthase (nNOS) phosphorylation, triggered by a reduction in cAMP, accounts for the NO/ADN-dependent reductions in RVLM oxidative stress and BP. Intra-RVLM GPR18 activation (Abn CBD; 0.4 mg) enhanced RVLM Akt, ERK1/2, and nNOS phosphorylation as well as ADN levels during the hypotensive response. Prior GPR18 blockade with O-1918 (1,3-dimethoxy-5-methyl-2-[(1R,6R)-3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]benzene) produced the opposite effects and abrogated Abn CBD-evoked neurochemical and BP responses. Pharmacological inhibition of RVLM phosphoinositide 3-kinase (PI3K)/Akt (wortmannin), ERK1/2 (PD98059 [2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one]), or nNOS (N v -propyl-Larginine), or activation of adenylyl cyclase (forskolin) virtually abolished intra-RVLM Abn CBD-evoked hypotension and the increases in Akt, ERK1/2, and nNOS phosphorylation and in ADN levels in the RVLM. Our pharmacological and neurochemical findings support a pivotal role for PI3K, Akt, ERK1/2, nNOS, and adenylyl cyclase, via modulation of NO, ADN, and cAMP levels, in GPR18 regulation of the RVLM redox state and BP in conscious rats.

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Section: Mechanisms For Central Gpr18-mediated Hypotensionsupporting

confidence: 87%

Neuronal Nitric Oxide Synthase–Dependent Elevation in Adiponectin in the Rostral Ventrolateral Medulla Underlies G Protein–Coupled Receptor 18–Mediated Hypotension in Conscious Rats

Penumarti

Abdel‐Rahman

2014

J Pharmacol Exp Ther

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“…In fact, levels of most AA-derived lipoamines measured here were lower in FAAH KO mice, such as NAGly, which was lower in all 8 regions. NAGly is an agonist at GPR18 [23, 66], drives microglial migration [67], and is antinociceptive and anti-inflammatory in several animal models of pain [18, 68, 69]. In mammalian cells, NAGly can be formed from AEA via two distinct pathways.…”

Section: Resultsmentioning

confidence: 99%

Broad impact of deleting endogenous cannabinoid hydrolyzing enzymes and the CB1 cannabinoid receptor on the endogenous cannabinoid-related lipidome in eight regions of the mouse brain

Leishman

Cornett

Spork

et al. 2016

Pharmacological Research

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Background and purpose The enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) hydrolyze endogenous cannabinoids (eCBs), N-arachidonoyl ethanolamine (AEA) and 2-arachidonoyl glycerol (2-AG), respectively. These enzymes also metabolize eCB analogs such as lipoamines and 2-acyl glycerols, most of which are not ligands at CB1. To test the hypothesis that deleting eCB hydrolyzing enzymes and CB1 shifts lipid metabolism more broadly and impacts more families of eCB structural analogs, targeted lipidomics analyses were performed on FAAH KO, MAGL KO, and CB1 KO mice and compared to WT controls in 8 brain regions. Experimental approach Methanolic extracts of discrete brain regions (brainstem, cerebellum, cortex, hippocampus, hypothalamus, midbrain, striatum and thalamus) were partially purified on C-18 solid-phase extraction columns. Over 70 lipids per sample were then analyzed with HPLC/MS/MS. Key results AEA and 2-AG were unaffected throughout the brain in CB1 KO mice; however, there was an increase in the arachidonic acid (AA) metabolite, PGE2 in the majority of brain areas. By contrast, PGE2 and AA levels were significantly reduced throughout the brain in the MAGL KO corresponding to significant increases in 2-AG. No changes in AA or PGE2 were seen throughout in the FAAH KO brain, despite significant increases in AEA, suggesting AA liberated by FAAH does not contribute to steady state levels of AA or PGE2. Changes in the lipidome were not confined to the AA derivatives and showed regional variation in each of the eCB KO models. Conclusions and implications AEA and 2-AG hydrolyzing enzymes and the CB1 receptor link the eCB system to broader lipid signaling networks in contrasting ways, potentially altering neurotransmission and behavior independently of cannabinoid receptor signaling.

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“…In fact, there is controversial evidence that anandamide and 2-AG may also activate GPR55, and the recent finding of CB1-GPR55 heteromers might explain why some authors have found that the 2 endocannabinoids directly activate this orphan GPCR and most others have not [43][44][45][46]. Another orphan GPCR, GPR18, is instead activated by N-arachidonoyl-glycine and by a synthetic CBD analogue known as abnormal-cannabidiol [47,48]. 2) Ttype Ca 2+ channels have been suggested to be inhibited by both unsaturated long chain fatty acid amides, including some N--acylethanolamines, N-acyl-serotonins, and N-acyldopamines [49], and THC and CBD [50].…”

Section: Other Ways Through Which Non-thc Plant Cannabinoids Influencmentioning

confidence: 99%

The Endocannabinoid System and its Modulation by Phytocannabinoids

2015

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The endocannabinoid system is currently defined as the ensemble of the two 7-transmembrane-domain and G protein-coupled receptors for Δ 9 -tetrahydrocannabinol (but not for most other plant cannabinoids or phytocannabinoids)-cannabinoid receptor type-1 (CB 1 R) and cannabinoid receptor type-2 (CB 2 R); their two most studied endogenous ligands, the "endocannabinoids" N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG); and the enzymes responsible for endocannabinoid metabolism. However, anandamide and 2-AG, and also the phytocannabinoids, have more molecular targets than just CB 1 R and CB 2 R. Furthermore, the endocannabinoids, like most other lipid mediators, have more than just one set of biosynthetic and degrading pathways and enzymes, which they often share with "endocannabinoid-like" mediators that may or may not interact with the same proteins as Δ 9 -tetrahydrocannabinol and other phytocannabinoids. In some cases, these degrading pathways and enzymes lead to molecules that are not inactive and instead interact with other receptors. Finally, some of the metabolic enzymes may also participate in the chemical modification of molecules that have very little to do with endocannabinoid and cannabinoid targets. Here, we review the whole world of ligands, receptors, and enzymes, a true "endocannabinoidome", discovered after the cloning of CB 1 R and CB 2 R and the identification of anandamide and 2-AG, and its interactions with phytocannabinoids.

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Activation of GPR18 by cannabinoid compounds: a tale of biased agonism

Cited by 135 publications

References 41 publications

Neuronal Nitric Oxide Synthase–Dependent Elevation in Adiponectin in the Rostral Ventrolateral Medulla Underlies G Protein–Coupled Receptor 18–Mediated Hypotension in Conscious Rats

Neuronal Nitric Oxide Synthase–Dependent Elevation in Adiponectin in the Rostral Ventrolateral Medulla Underlies G Protein–Coupled Receptor 18–Mediated Hypotension in Conscious Rats

Broad impact of deleting endogenous cannabinoid hydrolyzing enzymes and the CB1 cannabinoid receptor on the endogenous cannabinoid-related lipidome in eight regions of the mouse brain

The Endocannabinoid System and its Modulation by Phytocannabinoids

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