The novel endocannabinoid receptor GPR55 is activated by atypical cannabinoids but does not mediate their vasodilator effects

Dg, Johns; Behm, DJ; Dj, Walker; Zhang, Ao; Em, Shapland; Da, Daniels; Riddick, Maximiliano; Dowell, Simon J.; Pc, Staton; Green, P; Shabon, Usman; Bao, Wei; Aiyar, Nambi; Tl, Yue; Brown, Andrew J.; Ad, Morrison; Sa, Douglas

doi:10.1038/sj.bjp.0707419

Cited by 220 publications

(244 citation statements)

References 15 publications

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“…O-1602 significantly inhibited the late stages (including cell fusion) of osteoclastogenesis from mouse precursors. Although there is evidence that O-1602 can act on additional targets (13), in the present study the inhibitory effect of O-1602 on osteoclastogenesis was mediated via GPR55, because this effect was not observed in BMMs from GPR55 Ϫ/Ϫ mice but was retained in macrophages from CB 1 Ϫ/Ϫ and CB 2 Ϫ/Ϫ mice. Consistent with the inhibitory effect of O-1602 on mouse osteoclast formation in vitro, osteoclast number was significantly higher in the long bones from GPR55 Ϫ/Ϫ mice than in those from wild-type mice.…”

Section: Discussionmentioning

confidence: 69%

“…Using immunostaining and quantitative PCR, we demonstrate that both human and mouse osteoclasts and osteoblasts express GPR55 and that GPR55 mRNA is present in human monocytic osteoclast precursors but increases during differentiation into mature, multinucleated osteoclasts. To investigate the role of GPR55 in osteoclast formation, we used a synthetic GPR55 agonist, O-1602 (6,13). O-1602 significantly inhibited the late stages (including cell fusion) of osteoclastogenesis from mouse precursors.…”

Section: Discussionmentioning

confidence: 99%

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The putative cannabinoid receptor GPR55 affects osteoclast function in vitro and bone mass in vivo

Whyte

Ryberg

Sims

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

294

328

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GPR55 is a G protein-coupled receptor recently shown to be activated by certain cannabinoids and by lysophosphatidylinositol (LPI). However, the physiological role of GPR55 remains unknown. Given the recent finding that the cannabinoid receptors CB 1 and CB2 affect bone metabolism, we examined the role of GPR55 in bone biology. GPR55 was expressed in human and mouse osteoclasts and osteoblasts; expression was higher in human osteoclasts than in macrophage progenitors. Although the GPR55 agonists O-1602 and LPI inhibited mouse osteoclast formation in vitro, these ligands stimulated mouse and human osteoclast polarization and resorption in vitro and caused activation of Rho and ERK1/2. These stimulatory effects on osteoclast function were attenuated in osteoclasts generated from GPR55 ؊/؊ macrophages and by the GPR55 antagonist cannabidiol (CBD). Furthermore, treatment of mice with this non-psychoactive constituent of cannabis significantly reduced bone resorption in vivo. Consistent with the ability of GPR55 to suppress osteoclast formation but stimulate osteoclast function, histomorphometric and microcomputed tomographic analysis of the long bones from male GPR55 ؊/؊ mice revealed increased numbers of morphologically inactive osteoclasts but a significant increase in the volume and thickness of trabecular bone and the presence of unresorbed cartilage. These data reveal a role of GPR55 in bone physiology by regulating osteoclast number and function. In addition, this study also brings to light an effect of both the endogenous ligand, LPI, on osteoclasts and of the cannabis constituent, CBD, on osteoclasts and bone turnover in vivo.A role for the endocannabinoid system (1) in the regulation of bone mass has been demonstrated recently, because mice lacking either of the cannabinoid receptors CB 1 or CB 2 have abnormal bone phenotypes. Furthermore, cannabinoid receptor agonists and inverse agonists reduce bone loss in mice following ovariectomy and have direct effects on both bone-resorbing cells (osteoclasts) and bone-forming cells (osteoblasts) in vitro (2, 3).In some systems such as the vasculature, there is considerable evidence for a role of non-CB 1 /non-CB 2 receptors in mediating some of the effects of certain cannabinoid ligands (for review, see ref. 4). Such non-CB 1 /non-CB 2 effects have been observed with a range of cannabinoid ligands including certain endocannabinoids and the phytocannabinoid-like compound O-1602; these effects are antagonized by the cannabis constituent cannabidiol (CBD) (4). Recently, the G protein-coupled receptor GPR55 has been shown to be activated by O-1602 (EC 50 ϭ 13 nM) and antagonized by CBD (IC 50 ϭ 445 nM) (5-8). In contrast, these compounds have low affinity (5-30 M) for CB 1 and CB 2 receptors (9, 10). GPR55 also is activated by the bioactive lipid, L-␣-lysophosphatidylinositol (LPI) (11,12).The physiological role(s) of GPR55 remains unknown. Given the apparent role of CB 1 and CB 2 in regulating bone mass, we examined whether GPR55 is expressed by osteoblasts and osteoc...

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Section: Discussionmentioning

confidence: 69%

Section: Discussionmentioning

confidence: 99%

The putative cannabinoid receptor GPR55 affects osteoclast function in vitro and bone mass in vivo

Whyte

Ryberg

Sims

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

294

328

View full text Add to dashboard Cite

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“…GPR55 has been suggested to couple through G q , G 12 , and G 13 (9,11). Therefore, as a measure of GPR55-mediated G-protein signaling, we tested the ability of the agonists identified in this report, LPI, AM251, and rimonabant, to recruit PKC␤II to the plasma membrane or to produce membrane remodeling or blebbing (20,30).…”

Section: Gpr55 and Ha-gpr55 Recruit ␤Arr2-gfp In Response To Lpi-mentioning

confidence: 99%

“…GPR55 was first identified and mapped to human chromosome 2q37 a decade ago (8). In the human central nervous system, it is predominantly localized to the caudate, putamen, and striatum (8), coupling to G␣ 13 (9,10), G␣ 12 , or G␣ q (11).…”

mentioning

confidence: 99%

Atypical Responsiveness of the Orphan Receptor GPR55 to Cannabinoid Ligands

Kapur

Zhao

Sharir

et al. 2009

Journal of Biological Chemistry

251

289

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The cannabinoid receptor 1 (CB 1 ) and CB 2 cannabinoid receptors, associated with drugs of abuse, may provide a means to treat pain, mood, and addiction disorders affecting widespread segments of society. Whether the orphan G-protein coupled receptor GPR55 is also a cannabinoid receptor remains unclear as a result of conflicting pharmacological studies. GPR55 has been reported to be activated by exogenous and endogenous cannabinoid compounds but surprisingly also by the endogenous non-cannabinoid mediator lysophosphatidylinositol (LPI). We examined the effects of a representative panel of cannabinoid ligands and LPI on GPR55 using a ␤-arrestingreen fluorescent protein biosensor as a direct readout of agonist-mediated receptor activation. Our data demonstrate that AM251 and SR141716A (rimonabant), which are cannabinoid antagonists, and the lipid LPI, which is not a cannabinoid receptor ligand, are GPR55 agonists. They possess comparable efficacy in inducing ␤-arrestin trafficking and, moreover, activate the G-protein-dependent signaling of protein kinase C␤II. Conversely, the potent synthetic cannabinoid agonist CP55,940 acts as a GPR55 antagonist/partial agonist. CP55,940 blocks GPR55 internalization, the formation of ␤-arrestin GPR55 complexes, and the phosphorylation of ERK1/2; CP55,940 produces only a slight amount of protein kinase C␤II membrane recruitment but does not stimulate membrane remodeling like LPI, AM251, or rimonabant. Our studies provide a paradigm for measuring the responsiveness of GPR55 to a variety of ligand scaffolds comprising cannabinoid and novel compounds and suggest that at best GPR55 is an atypical cannabinoid responder. The activation of GPR55 by rimonabant may be responsible for some of the off-target effects that led to its removal as a potential obesity therapy.The CB 1 2 and CB 2 cannabinoid receptors comprise a twomember subfamily of G-protein-coupled receptors (GPCRs) that are notable as the targets of the tetrahydrocannabinol (THC) derivatives found in marijuana. More recently CB 1 receptors along with other GPCRs have been promoted as therapeutic pharmacological targets in the billion dollar weight loss market for controversial drugs such as rimonabant (SR141716A) and Fen-phen. Thus, an important utility of cannabinoid family receptors to society appears to arise from their role in regulating a broad spectrum of addiction-based behaviors, and the addition of new members to the cannabinoid receptor family may have social and economic implications that reach far beyond the initial scientific discovery. As a consequence, the re-classification of an orphan GPCR as a cannabinoid family member should be done with caution requiring strict criteria of receptor activation by THC derivatives or endogenous cannabinoid compounds and a widespread agreement of the results by the scientific community.Marijuana, one of the most widely abused substances (1), mediates many of its psychotropic effects by targeting CB 1 receptors in the central nervous system, but studies with CB 1 and CB 2 kno...

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“…Mice with a target deletion of the GPR55 gene show no specific phenotype. 49 GPR55 is has been found to be widely expressed in the brain, especially in the cerebellum. It is found in the gastrointestinal tract in the jejunum and ileum and also in the adrenal glands but is apparently not highly expressed elsewhere in the periphery.…”

Section: Cannabinoid Receptorsmentioning

confidence: 99%

Synthesis of Novel Cannabinoid Ligands and Their Use as Anti-Glioma and Anti-Inflammatory Agents

Gurley¹

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The novel endocannabinoid receptor GPR55 is activated by atypical cannabinoids but does not mediate their vasodilator effects

Cited by 220 publications

References 15 publications

The putative cannabinoid receptor GPR55 affects osteoclast function in vitro and bone mass in vivo

The putative cannabinoid receptor GPR55 affects osteoclast function in vitro and bone mass in vivo

Atypical Responsiveness of the Orphan Receptor GPR55 to Cannabinoid Ligands

Synthesis of Novel Cannabinoid Ligands and Their Use as Anti-Glioma and Anti-Inflammatory Agents

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