Integrin clustering enables anandamide-induced Ca2+ signaling in endothelial cells via GPR55 by protection against CB1-receptor-triggered repression

Waldeck-Weiermair, Markus; Zoratti, Cristina; Osibow, Karin; Balenga, Nariman; Goessnitzer, Edith; Waldhoer, Maria; Malli, Roland; Graier, Wolfgang F.

doi:10.1242/jcs.020958

Cited by 167 publications

(194 citation statements)

References 97 publications

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“…Previous studies have highlighted the involvement of the cannabinoid receptors CB 1 and CB 2 in the local and/or central control of bone mass (2,3,33). Opinion is divided as to whether endocannabinoids have the ability to act as agonists of GPR55 (6,11,12,19,26), but our findings introduce the possibility that the effect of certain endocannabinoids on bone cells may be mediated, at least in part, via GPR55. Lysophospholipids play a role in many physiological and pathophysiological processes and now are recognized as extracellular signaling molecules as well as precursors of phospholipid synthesis (34).…”

Section: Discussionmentioning

confidence: 70%

“…LPI (and, to a lesser extent, O-1602) also caused activation of ERK in osteoclasts; ERK is associated with increased osteoclast activity and survival (23)(24)(25). Although some studies have failed to show that ERK lies downstream of GPR55 (19), other studies have demonstrated robust GPR55-mediated ERK activation (11,26). The contradictory nature of these findings may relate to the concept of functional selectivity (27,28), whereby different signaling pathways (e.g., Rho and ERK) are activated in an agonist-and tissue-specific manner (8).…”

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.

293

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: 70%

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.

293

328

View full text Add to dashboard Cite

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“…Studies in mice lacking GPR55 have reported a reduction in inflammatory and neuropathic pain (1), and these mice have increased bone mass (2). Subsequently, studies have established that the endogenous lysophospholipid LPI 2 activates GPR55 (3)(4)(5)(6)(7)(8)(9)(10). In certain cancer cell lines, GPR55 is highly expressed, and LPI mediates increased cell migration, invasion, and proliferation (3,8,11).…”

mentioning

confidence: 99%

Modulation of l-α-Lysophosphatidylinositol/GPR55 Mitogen-activated Protein Kinase (MAPK) Signaling by Cannabinoids

Anavi‐Goffer

Baillie

Irving

et al. 2012

Journal of Biological Chemistry

137

132

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Background:The endogenous L-␣-lysophosphatidylinositol activates GPR55. Results: Structural analogues of SR141716A act both as agonists alone and as inhibitors of L-␣-lysophosphatidylinositol. Certain CB 2 receptor agonists also modulate GPR55 activity. Conclusion: Certain cannabinoids can both activate GPR55 and attenuate L-␣-lysophosphatidylinositol-mediated phosphorylated ERK1/2 activation. This has mechanistic implications for the antinociceptive effects of certain CB 2 agonists. Significance: Cannabinoid ligands have complex interactions with the L-␣-lysophosphatidylinositol/GPR55 signaling system.

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“…They observed that integrin clusterings in the periphery of the cell occur within minutes, starts about after 3 minutes. There are also many recent studies on integrin clustering, such as by [19,48,39,52,55,2,25,45].…”

Section: Structural Components Of Cell-matrix Adhesionmentioning

confidence: 99%

Intracellular Modelling of Cell-Matrix Adhesion during Cancer Cell Invasion

Andasari

Chaplain

2012

Math. Model. Nat. Phenom.

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Abstract. When invading the tissue, malignant tumour cells (i.e. cancer cells) need to detach from neighbouring cells, degrade the basement membrane, and migrate through the extracellular matrix. These processes require loss of cell-cell adhesion and enhancement of cell-matrix adhesion. In this paper we present a mathematical model of an intracellular pathway for the interactions between a cancer cell and the extracellular matrix. Cancer cells use similar mechanisms as with normal cells for their interactions with the extracellular matrix. We develop a model of cell-matrix adhesion that accounts for reactions between the cell surface receptor integrins, the matrix glycoprotein fibronectin, and the actin filaments in the cytoskeleton. Each represents components for an intermediate compartment, the extracellular compartment, and the intracellular compartment, respectively. Binding of fibronectin with integrins triggers a clustering of protein complexes, which then activates and phosphorylates regulatory proteins that are involved in actin reorganisation causing actin polymerization and stress fibre assembly. Rearrangement of actin filaments with integrin/fibronectin complexes near adhesion sites and interaction with fibrillar fibronectin produces the force necessary for cell migration, accounting for cell-matrix adhesion.

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Integrin clustering enables anandamide-induced Ca2+ signaling in endothelial cells via GPR55 by protection against CB1-receptor-triggered repression

Cited by 167 publications

References 97 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

Modulation of l-α-Lysophosphatidylinositol/GPR55 Mitogen-activated Protein Kinase (MAPK) Signaling by Cannabinoids

Intracellular Modelling of Cell-Matrix Adhesion during Cancer Cell Invasion

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