The enigmatic pharmacology of GPR55 Ross, Ruth A
Trends in pharmacological sciences (Regular ed.),
03/2009, Volume:
30, Issue:
3
Journal Article
Peer reviewed
Preliminary data presented at conferences and in the patent literature introduced the possibility the orphan receptor GPR55 might account for some of the well-documented non-CB1 , non-CB2 effects ...reported for certain cannabinoid ligands. Several peer-reviewed publications have recently emerged in which the pharmacology of the cannabinoids at GPR55 has been probed in more depth. Despite this, the classification of GPR55 as a cannabinoid receptor remains a contentious issue. The weight of evidence points to GPR55 as a receptor that is activated by certain cannabinoid ligands and by the bioactive lipid l -α-lysophosphatidylinsoitol. It couples to G12 proteins, activates RhoA and mobilizes intracellular Ca2+ , possibly in an agonist- and tissue-dependant manner, thus displaying ‘agonist functional selectivity’. Here, I review the recent literature in an effort to glean the key controversies and outstanding questions surrounding the interaction between cannabinoids and this orphan receptor.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
A large body of evidence now exists to substantiate that the endocannabinoid, anandamide, activates TRPV1 receptors. It is a low intrinsic efficacy TRPV1 agonist that behaves as a partial agonist in ...tissues with a low receptor reserve, while in tissues with high receptor reserve and in circumstances associated with certain disease states, it behaves as a full agonist. The efficacy of anandamide as a TRPV1 agonist is influenced by a succession of factors including receptor reserve, phosphorylation, metabolism and uptake, CB1 receptor activation, voltage, temperature, pH and bovine serum albumin. There are indications that the endocannabinoid system may play a role in the modulation of TRPV1 receptor activation. The activation of TRPV1 receptors by anandamide has potential implications in the treatment of inflammatory, respiratory and cardiovascular disorders. The relative importance of anandamide as a physiological and/or pathophysiological TRPV1 receptor agonist in comparison to other potential candidates has yet to be revealed.
British Journal of Pharmacology (2003) 140, 790–801. doi:10.1038/sj.bjp.0705467
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G protein-coupled receptor (GPR) 55 is sensitive to certain cannabinoids, it is expressed in the brain and, in cell cultures, it triggers mobilization of intracellular Ca ²⁺. However, the adaptive ...neurobiological significance of GPR55 remains unknown. Here, we use acute hippocampal slices and combine two-photon excitation Ca ²⁺ imaging in presynaptic axonal boutons with optical quantal analysis in postsynaptic dendritic spines to find that GPR55 activation transiently increases release probability at individual CA3-CA1 synapses. The underlying mechanism involves Ca ²⁺ release from presynaptic Ca ²⁺ stores, whereas postsynaptic stores (activated by spot-uncaging of inositol 1,4,5-trisphosphate) remain unaffected by GPR55 agonists. These effects are abolished by genetic deletion of GPR55 or by the GPR55 antagonist cannabidiol, a constituent of Cannabis sativa . GPR55 shows colocalization with synaptic vesicle protein vesicular glutamate transporter 1 in stratum radiatum. Short-term potentiation of CA3-CA1 transmission after a short train of stimuli reveals a presynaptic, Ca ²⁺ store-dependent component sensitive to cannabidiol. The underlying cascade involves synthesis of phospholipids, likely in the presynaptic cell, but not the endocannabinoids 2-arachidonoylglycerol or anandamide. Our results thus unveil a signaling role for GPR55 in synaptic circuits of the brain.
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To evaluate midterm outcomes of arthroscopic superior capsular reconstruction (SCR) using a decellularized porcine dermal xenograft in patients with massive, irreparable rotator cuff tears and to ...determine the influence of concomitant, repairable subscapularis tears.
This is a retrospective study of 56 patients with a minimum 2-year follow-up. Preoperative and postoperative range of motion, American Shoulder and Elbow Surgeons score, Subjective Shoulder Value, and visual analog score for pain were measured. Postoperative data were collected at 3, 6, 12, 24, and 36 months.
Of the 56 patients who underwent arthroscopic SCR, there were 39 men and 17 women. The mean age at operation was 65 ± 9 years, and the mean follow-up was 34 ± 8 months. The mean preoperative American Shoulder and Elbow Surgeons improved from 41 ± 19 to 78 ± 18 at 24 weeks, to 86± 16 at 12 months, and to 90±9 at 24 months, P < .0001. Similarly, the mean preoperative Subjective Shoulder Value improved from 39 ± 17 to 74 ± 18 at 24 weeks, to 80 ± 18 at 12 months, and to 80 ± 11 at 24 months, P < .0001. The mean preoperative visual analog score improved from 6.5 ± 2.1 to 1.4 ± 2.2 at 24 weeks, to 0.7± 1.1 at 12 months, and to 0.2 ± 0.4 at 24 months, P < .0001. There were no differences in outcome scores between patients with intact vs. repaired subscapularis. Similarly, no statistically significant differences were found in forward flexion or external rotation after SCR between patients with an intact vs. repaired subscapularis. Failure of the SCR graft was observed on magnetic resonance imaging in 14 patients, 4 of whom opted for revision to reverse shoulder arthroplasty. Eleven patients were truly pseudoparalytic before surgery; in 5 cases, pseudoparalysis was reversed after SCR.
SCR can alleviate pain and disability from irreparable rotator cuff tears and provide significant improvements in shoulder function; however, the xenograft technique resulted in inconsistent reversal of true pseudoparalysis. No difference was found between patients who required concomitant subscapularis repair vs. those who did not.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Evidence points to a role of L-α-lysophosphatidylinositol (LPI) in cancer. First, clinical data identified LPI as a biomarker for poor prognosis in cancer patients. Second, in vitro studies ...demonstrated significantly elevated levels of LPI in highly proliferative cancer cells. Third, LPI displays mitogenic activity in cancer cell lines, in which the lipid significantly increased cell proliferation. However, a receptor target for LPI remained elusive until very recently. It has now been revealed that LPI activates GPR55, a G protein-coupled receptor that couples to G12/13 and Gq proteins, which direct oncogenic signalling. New evidence indicates that LPI and GPR55 are key partners in driving cancer cell proliferation and migration. GPR55 is expressed in human tumours and drives proliferation and its expression correlates with tumour aggressiveness. Overall patient survival is lower in patients whose glioblastomas express higher levels of GPR55. Thus, evidence suggests that interaction with GPR55 might underlie the pro-tumoural actions of LPI.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Parkinson's disease (PD) is a common chronic neurodegenerative disorder, usually of idiopathic origin. Symptoms including tremor, bradykinesia, rigidity and postural instability are caused by the ...progressive loss of dopaminergic neurons in the nigrostriatal region of the brain. Symptomatic therapies are available but no treatment slows or prevents the loss of neurons. Neuroinflammation has been implicated in its pathogenesis. To this end, the present study utilises the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin to reproduce the pattern of cell death evident in PD patients. Herein, the role of a potential regulator of an immune response, the endocannabinoid system (ECS), is investigated. The most prevalent endocannabinoid, 2-arachidonoylglycerol (2-AG) (3 and 5mg/kg), was added exogenously and its enzymatic degradation inhibited to provide protection against MPTP-induced cell death. Furthermore, the addition of DFU (25mg/kg), a selective inhibitor of inflammatory mediator cyclooxygenase-2 (COX-2), potentiated these effects. Levels of 2-AG were shown to be upregulated in a time- and region-specific manner following MPTP administration, indicating that the ECS represents a natural defence mechanism against inflammation, potentiation of which could provide therapeutic benefits. The results expand the current understanding of the role that this signalling system has and its potential influence in PD.
•We investigate the role of 2-AG in a model of Parkinson's disease.•2-AG and inhibition of its metabolism by JZL184 protected against MPTP toxicity.•A combination of JZL184 with a COX-2 inhibitor increased the effect.•Manipulation of endocannabinoid levels might be useful for Parkinson's disease.
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The roles of endocannabinoid signaling during central nervous system development are unknown. We report that CB₁ cannabinoid receptors (CB₁Rs) are enriched in the axonal growth cones of ...γ-aminobutyric acid-containing (GABAergic) interneurons in the rodent cortex during late gestation. Endocannabinoids trigger CB₁R internalization and elimination from filopodia and induce chemorepulsion and collapse of axonal growth cones of these GABAergic interneurons by activating RhoA. Similarly, endocannabinoids diminish the galvanotropism of Xenopus laevis spinal neurons. These findings, together with the impaired target selection of cortical GABAergic interneurons lacking CB₁Rs, identify endocannabinoids as axon guidance cues and demonstrate that endocannabinoid signaling regulates synaptogenesis and target selection in vivo.
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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 CB₁ 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.
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The first generation of CB1 positive allosteric modulators (e.g., ZCZ011) featured a 3-nitroalkyl-2-phenyl-indole structure. Although a small number of drugs include the nitro group, it is generally ...not regarded as being “drug-like”, and this is particularly true for aliphatic nitro groups. There are very few case studies where an appropriate bioisostere replaced a nitro group that had a direct role in binding. This may be indicative of the difficulty of replicating its binding interactions. Herein, we report the design and synthesis of ligands targeting the allosteric binding site on the CB1 cannabinoid receptor, in which a CF3 group successfully replaced the aliphatic NO2. In general, the CF3-bearing compounds were more potent than their NO2 equivalents and also showed improved in vitro metabolic stability. The CF3 analogue (1) with the best balance of properties was selected for further pharmacological evaluation. Pilot in vivo studies showed that (±)-1 has similar activity to (±)-ZCZ011, with both showing promising efficacy in a mouse model of neuropathic pain.
Endocannabinoids and some phytocannabinoids bind to CB1 and CB2 cannabinoid receptors, transient receptor potential vanilloid one (TRPV1) receptor and the orphan G protein receptor fifty-five ...(GPR55). Studies using C57BL/10 and C57BL/6 (Cnr2 (tm1Zim)) CB2 cannabinoid receptor knockout mice have demonstrated an immune-augmenting effect in experimental autoimmune encephalomyelitis (EAE) models of multiple sclerosis. However, other EAE studies in Biozzi ABH mice often failed to show any treatment effect of either CB2 receptor agonism or antagonism on inhibition of T cell autoimmunity. The influence of genetic background on the induction of EAE in endocannabinoid system-related gene knockout mice was examined. It was found that C57BL/6.GPR55 knockout mice developed less severe disease, notably in female mice, following active induction with myelin oligodendrocyte glycoprotein 35-55 peptide. In contrast C57BL/6.CB2 (Cnr2 (Dgen)) receptor knockout mice developed augmented severity of disease consistent with the genetically and pharmacologically-distinct, Cnr2 (tm1Zim) mice. However, when the knockout gene was bred into the ABH mouse background and EAE induced with spinal cord autoantigens the immune-enhancing effect of CB2 receptor deletion was lost. Likewise CB1 receptor and transient receptor potential vanilloid one knockout mice on the ABH background demonstrated no alteration in immune-susceptibility, in terms of disease incidence and severity of EAE, in contrast to that reported in some C57BL/6 mouse studies. Furthermore the immune-modulating influence of GPR55 was marginal on the ABH mouse background. Whilst sedative doses of tetrahydrocannabinol could induce immunosuppression, this was associated with a CB1 receptor rather than a CB2 receptor-mediated effect. These data support the fact that non-psychoactive doses of medicinal cannabis have a marginal influence on the immune response in MS. Importantly, it adds a note of caution for the translational value of some transgenic/gene knockout and other studies on low-EAE susceptibility backgrounds with inconsistent disease course and susceptibility.
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