Jump to ContentJump to Main Navigation
Show Summary Details
More options …

Journal of Basic and Clinical Physiology and Pharmacology

Editor-in-Chief: Horowitz, Michal

Editorial Board: Das, Kusal K. / Epstein, Yoram / S. Gershon MD, Elliot / Haim, Abraham / Kodesh , Einat / Kohen, Ron / Lichtstein, David / Maloyan, Alina / Mechoulam, Raphael / Roth, Joachim / Schneider, Suzanne / Shohami, Esther / Sohmer, Haim / Yoshikawa, Toshikazu

6 Issues per year


CiteScore 2016: 1.01

SCImago Journal Rank (SJR) 2016: 0.349
Source Normalized Impact per Paper (SNIP) 2016: 0.495

Online
ISSN
2191-0286
See all formats and pricing
More options …
Volume 27, Issue 3

Issues

GPR55 – a putative “type 3” cannabinoid receptor in inflammation

Hyewon Yang
  • Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada
  • Department of Anesthesia, Pain Management and Perioperative Medicine, Dalhousie University, Halifax, Nova Scotia, Canada
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Juan Zhou
  • Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada
  • Department of Anesthesia, Pain Management and Perioperative Medicine, Dalhousie University, Halifax, Nova Scotia, Canada
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Christian Lehmann
  • Corresponding author
  • Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada
  • Department of Anesthesia, Pain Management and Perioperative Medicine, Dalhousie University, Halifax, Nova Scotia, Canada
  • Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada
  • Email
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
Published Online: 2015-12-15 | DOI: https://doi.org/10.1515/jbcpp-2015-0080

Abstract

G protein-coupled receptor 55 (GPR55) shares numerous cannabinoid ligands with CB1 and CB2 receptors despite low homology with those classical cannabinoid receptors. The pharmacology of GPR55 is not yet fully elucidated; however, GPR55 utilizes a different signaling system and downstream cascade associated with the receptor. Therefore, GPR55 has emerged as a putative “type 3” cannabinoid receptor, establishing a novel class of cannabinoid receptor. Furthermore, the recent evidence of GPR55-CB1 and GPR55-CB2 heteromerization along with its broad distribution from central nervous system to peripheries suggests the importance of GPR55 in various cellular processes and pathologies and as a potential therapeutic target in inflammation.

Keywords: CB2; endocannabinoid system; GPR55; immune modulation; inflammation; sepsis

Introduction

The endocannabinoid system (ECS) has a tremendous potential for experimental and clinical research, based on their ubiquitary presence in vertebrates and role in fundamental physiological and pathological processes, including pain modulation, immune function, neuroprotection, cancer, cardiovascular diseases, fertility and appetite [1]. Clinical studies using cannabinoid receptor agonists and antagonists have suggested their possible use in modulating acute and/or chronic diseases, e.g. hypertension, glaucoma, emesis, anxiety, depression, gastrointestinal and hepatic disorders, ulcerative colitis and neuropathic and inflammatory pain [2, 3].

The evidence for homeostatic and protective functions of endocannabinoids in inflammation encourages studies of ECS as a therapeutic target in sepsis. Further elucidation of endocannabinoid signaling pathways will aid in the design of compounds with site specificity and high affinity to various receptor targets [4, 5]. In this review, current knowledge of the expression and function of the orphan G protein-coupled receptor 55 (GPR55), a putative “CB3” receptor, is summarized, highlighting its potential to be a therapeutic target in inflammation.

Endocannabinoid system

The marijuana plant, Cannabis sativa, has been used for more than 4000 years for a variety of purposes from medicine to recreation owing to their psychoactive properties. There are over 80 active phytocannabinoids in the marijuana plant, which exert their effects on the central and peripheral nervous system by binding and activating specific receptors in the cell membrane [6]. The most prominent and best-investigated phytocannabinoids from C. sativa are Δ9-tetrahydrocannabidiol (THC) and cannabidiol [7]. Although these phytocannabinoids have been studied extensively for their psychoactive properties, their potential use as therapeutic agents have been undermined until the discovery of the ECS in the early 1990s [6].

The ECS consists of three components: endogenous lipid-signaling molecules (endocanabinoids), G protein-coupled cannabinoid receptors and the enzymes for biosynthesis and degradation. Endocannabinoids are endogenous agonists of cannabinoid receptors and are found to mimic the pharmacological actions of the phytocannabinoids [6, 8]. The first identified endocannabinoid was N-arachidonyl ethanolamine (anadamide or AEA) in 1992, followed by 2-arachidonyl (2-AG) in 1995, which are the best-studied endocannabinoids to date [9, 10].

Biosynthesis of endocannabinoids takes place on demand either by activity-dependent or receptor- stimulated cleavage of arachidonic acid in the cell membrane, which activates enzymes including N-acyl-phosphatidylethanol- amine-hydrolyzing phospholipase D for AEA synthesis and two isoforms of diacylglycerol lipases (DAGLα and DAGLβ) for 2-AG synthesis [11, 12]. Because of the lipophilic nature of endocannabinoids, they are not suitable for storage in vesicles and thus are released immediately after their production. Followed by the biosynthesis, these lipid transmitters then locally activate cannabinoid receptors in response to different physiological and pathological stimuli [5].

Endocannabinoids are degradated by enzymatic hydrolysis mediated by specific intracellular enzymes to limit excessive endocannabinoid signaling. The major degradation enzymes responsible for these reactions have been identified as fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), for AEA and 2-AG, respectively [13, 14]. To inhibit the degradation of endocannabinoids, enzyme inhibitors are developed. The most well-characterized inhibitors of degradation enzymes are URB597 and JZL184 for inhibiting FAAH and MAGL degradation, respectively [15, 16].

The cannabinoid receptors are members of seven-transmembrane spanning class A G protein-coupled receptor (GPCR) subfamily. In the late 1980s and early 1990s, two high-affinity cannabinoid receptors that bind anandamide and 2-AG have been identified by molecular cloning: cannabinoid receptor type 1 and type 2 (CB1 and CB2) [1719]. CB1 receptors are predominantly expressed in the central nervous system (CNS) and mediate most psychoactive effects, whereas CB2 receptors are mainly distributed in peripheral and immune cells, mediating immunosuppressive effects [1921]. When activated by endocannabinoids, both CB1 and CB2 receptors are coupled to Gi/o heteromeric G protein and thereby inhibit adenylyl cyclase, activate mitogen-activated protein kinases and further turn on numerous transcription factors [5].

The discovery of cannabinoid receptors is followed by development of selective CB1 and CB2 receptor agonists and antagonists [22]. The best known of CB1-selective agonists include R-(+)-methanandamide, arachidonyl-2′-chloroethylamide, arachidonyl-cyclopropylamide and O-1812, and antagonists are AM251 and AM281. As for CB2-selective receptors, there are JWH133, HU308 and AM1241 for agonists and SR144528 and AM630 for antagonists [6]. Compounds such as (–) 11-hydroxy-Δ8-THC-dimethylheptyl (HU-210), CP55940, and R-(+)-WIN55212 are able to activate both CB1 and CB2 receptors [6].

GPR55 expression and signaling

In the last decade, accumulating evidence from studies using either selective CB1 and CB2 ligands or CB1 and/or CB2 knockout mice has suggested the existence of one or more additional cannabinoid receptors distinct from CB1 and CB2 receptors [23]. Recently, the orphan GPR55 showed binding with some cannabinoids and non-cannabinoid ligands and therefore presented as the main candidate to be considered as the “third” cannabinoid receptor [24].

In 1999, Sawzdargo et al. first isolated and cloned human GPR55 (hGPR55) with high expression in the regions of the CNS including the hippocampus, caudate, putamen, hypothalamus, cerebellum, thalamus and pons. It is also expressed in peripheral tissues such as the endothelial cells, adrenal glands and gastrointestinal tract [24, 25]. More recently, high expression of GPR55 is also found on lymphocytes and spleen, as well as on many cancer cells, which correlates with the rate of cancer cell proliferation [26, 27]. Although GPR55 shares several cannabinoid ligands with CB1 and CB2, GPR55 exhibits a low amino acid identity to CB1 (13.5%) and CB2 (14.4%). However, GPR55 is clearly a member of class A GPCRs, based on amino acid homology with P2Y5 purinergic receptor (29%), GPR23 (30%) and GPR35 (27%) [25].

The endocannabinoid receptor signaling pathways are not yet fully elucidated. The classical CB1 and CB2 signaling are known to utilize primarily Gαi/o heteromeric proteins and adenylate cyclase to activate multiple different downstream cascades. However, it is currently found that the signal transduction pathway of GPR55 differs from that of CB1 and CB2. It has been found that GPR55 only couples to Gα12,13 proteins, thereby activating ras homologue gene family member A (RhoA) and Rho-associated protein kinase (ROCK). Activation of RhoA and ROCK elicits phospholipase C (PLC) pathway to increase intracellular Ca2+, activates small GTPase proteins rhoA, Rac and cdc42, and turns on extracellular regulated kinase (ERK) phosphorylation (Figure 1) [24, 28, 29].

Overview of the GPR55 signaling pathway by LPI. Extracellular LPI can bind and activate GPR55. Activation of GPR55 is coupled to Gα12,13 proteins, thereby activating ras homologue gene family member A (RhoA) and ROCK. ROCK then turns on PLC pathway, which allows cytosolic concentration of Ca2+ to increase. Increased intracellular Ca2+ in turn leads to ERK phosphorylation and gene expression [24, 28, 29].
Figure 1:

Overview of the GPR55 signaling pathway by LPI.

Extracellular LPI can bind and activate GPR55. Activation of GPR55 is coupled to Gα12,13 proteins, thereby activating ras homologue gene family member A (RhoA) and ROCK. ROCK then turns on PLC pathway, which allows cytosolic concentration of Ca2+ to increase. Increased intracellular Ca2+ in turn leads to ERK phosphorylation and gene expression [24, 28, 29].

GPR55 pharmacology

Despite the low homology with the classical cannabinoid receptors (CB1 and CB2), several cannabinoids are found to interact with GPR55, including the cannabinoid agonist, Δ9-THC, CB1-selective antagonist/inverse agonist rimonabant and CB1 and CB2 agonist CP55, 940 [30]. It has been shown that 1-lysophosphatidylinositol (LPI), O-1602 and AM251 have agonist effects for GPR55, whereas SR141716A (Rimonabant), O-1918 and cannabidiol (CBD) have antagonist effects [3133]. However, there is controversial evidence regarding the opposite or divergent pharmacological effects through GPR55 compared to CB receptors [34]. For instance, anandamide and 2-AG are reported to activate GPR55, while other groups failed to detect the agonist effect by these cannabinoids [29, 34, 35].

Most recent studies on receptor coupling and heteromer formation present an explanation of the aforementioned controversial findings on GPR55 ligands [33, 36, 37]. Inconsistent activities of GPR55 is observed in response to cannabinoid ligands, influenced by the assay used to assess receptor function [33]. With that regard, a novel label-free assay is evaluated and successfully detected agonist activity for all GPR55 ligands tested [33]. Furthermore, it is reported that CB1 and other class A GPCRs could form homomers and heteromers, which alter the biochemical property of the receptors. Naturally co-expressed receptors are present in several cell types. For example, GPR55 and CB2 are co-expressed on neutrophils and cancer cells [37], and GPR55 and CB1 are co-expressed in several brain regions [36]. In these co-expression assays, GPR55-mediated signaling is inhibited with inactive CB1; in contrast, CB1-mediated signaling is enhanced with GPR55 [36]. On the other hand, the activation of GPR55 heteromers with CB2 receptor in cancer cells is ligand concentration dependent [37]. Furthermore, GPR55-CB2 heteromers are shown to elicit different pathways via ligand- and concentration-specific crosstalk (Figure 2) [38]. Overall, GPR55 heteromers with either CB1 or CB2 exhibit function as novel signaling entities [36, 37].

Schematic of signaling modulation of GPR55-CB2 heteromer. (A) CB2 signaling pathway is inhibited in the heteromer when both GPR55 and CB2 are activated by the agonists (negative crosstalk). (B) GPR55 antagonist inhibits CB2 agonist-induced heteromer activation (left) or CB2 antagonist inhibits GPR55 agonist-induced heteromer activation (right, cross antagonism) [37, 38].
Figure 2:

Schematic of signaling modulation of GPR55-CB2 heteromer.

(A) CB2 signaling pathway is inhibited in the heteromer when both GPR55 and CB2 are activated by the agonists (negative crosstalk). (B) GPR55 antagonist inhibits CB2 agonist-induced heteromer activation (left) or CB2 antagonist inhibits GPR55 agonist-induced heteromer activation (right, cross antagonism) [37, 38].

GPR55 in inflammation

GPR55 is widely distributed throughout the body, and its role has been suggested to be involved in many physiological and pathophysiological processes, including the role in pathophysiology of the gut [3941], inflammatory and neuropathic pain [42] and modulation of innate and adaptive immune system [4345].

As GPR55 is expressed throughout the rodent gastrointestinal tract, many gastrointestinal disease models were adopted to reveal the role of GRP55 in intestinal inflammation. For example, increased expression of GPR55 is observed in lipopolysaccharide (LPS)-treated intestine [41] in vivo suggesting GPR55 involvement in intestinal inflammation. In addition, GPR55 knockout mice showed less severe colitis compared to CB1 or CB2 knockout mice, suggesting pro-inflammatory role of GPR55 in experimental colitis induced by dextran sulfate sodium [39]. In another experimental colitis model, an endogenous anandamide-related lipid, palmitoylethanolamide (PEA), is shown to reduce neuro-inflammation and chronic pain in the colitis induced by intracolonic administration of dinitrobenzenesulfonic acid [46]. In this study, mRNA expression of GPR55 is significantly increased compared to CB2 when PEA is administered [46]. Furthermore, in a mechanical hyperalgesia model using Freund’s complete adjuvant, inflammation and neuropathic hypersensitivity are absent in GPR55 knockout mice, suggesting a pro-inflammatory role of GPR55 [42].

While the role of GPR55 was not fully elucidated, CB2R has been thought to be responsible for activation and recruitment of neutrophils as well as regulation of other immune cells. Recently, Balenga and colleagues found that GPR55 is involved in neutrophil chemotaxis and recruitment via crosstalk with CB2R orchestrated by various chemoattractants in downstream signaling pathway [43]. The interplay between GPR55 and CB2R during inflammation enhances neutrophil migration efficiency and revokes degranulation and ROS formation in neutrophils [43]. Moreover, GPR55 found on mast cells exerts its anti-inflammatory effect by inhibiting mast cell-mediated release of nerve growth factor and attenuating angiogenesis [44]. Lastly, it has been reported that GPR55 is highly expressed on monocytes and natural killer (NK) cells, compared to several innate and adaptive immune cells from human peripheral blood mononuclear cells [45]. Activation of LPS-activated monocytes and NK cells by GPR55 shows increase in pro-inflammatory cytokines, cytolytic activity of NK cells and decrease in endocytic activity of monocytes [45]. Altogether, these evidences remark on the potential role of GPR55 in innate immunity modulation and inflammation. Therefore, GPR55 is a novel candidate for treatment of inflammatory diseases.

Conclusions

The ECS is under investigation as an attractive target of drug development for inflammatory diseases. Cannabinoid receptor expression in different tissues and cells, along with their high affinity to bind cannabinoid ligands, contributes to their ability to modulate numerous cellular processes and pathologies.

GPR55, a putative “type 3” cannabinoid receptor, triggers distinct signaling pathways in response to inflammatory mediators. Although recent studies have rapidly expanded G protein-coupled receptor pharmacology and pathophysiology, more research for selective agonists and antagonists is required to resolve the controversial pharmacology of GPR55. In addition, biochemical insights in the receptor coupling and in vivo studies in knock-out mice will aid to further elucidate GPR55 mechanism of action and to develop specific GPR55 agonists and antagonists for the use in inflammation.

Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

Research funding: None declared.

Employment or leadership: None declared.

Honorarium: None declared.

Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

References

  • 1.

    Ligresti A, Petrosino S, Di Marzo V. From endocannabinoid profiling to endocannabinoid therapeutics. Curr Opin Chem Biol 2009;13:321–31. Google Scholar

  • 2.

    Di Marzo V. The endocannabinoid system: its general strategy of action, tools for its pharmacological manipulation and potential therapeutic exploitation. Pharmacol Res 2009;60:77–84. Web of ScienceGoogle Scholar

  • 3.

    McPartland JM, Guy GW, Di Marzo V. Care and feeding of the endocannabinoid system: a systematic review of potential clinical interventions that upregulate the endocannabinoid system. PLoS One 2014;9:e89566. Google Scholar

  • 4.

    Pacher P, Batkai S, Kunos G. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol Rev 2006;58:389–462. Google Scholar

  • 5.

    Battista N, Di Tommaso M, Bari M, Maccarrone M. The endocannabinoid system: an overview. Front Behav Neurosci 2012;6:9. Google Scholar

  • 6.

    Pertwee RG. The pharmacology of cannabinoid receptors and their ligands: an overview., Int J Obes (Lond) 2006;30:Suppl 1:S13–8. Google Scholar

  • 7.

    Gaoni Y, Mechoulam R. Isolation, structure and partial synthesis of an active constituent of hashish. J Am Chem Soc 1964;86:1646–7. Google Scholar

  • 8.

    Mechoulam R. Discovery of endocannabinoids and some random thoughts on their possible roles in neuroprotection and aggression. Prostaglandins Leukot Essent Fatty Acids 2002;66:93–9. Google Scholar

  • 9.

    Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 1992;258:1946–9. Google Scholar

  • 10.

    Mechoulam R, Ben-Shabat S, Hanus L, Ligumsky M, Kaminski NE, Schatz AR, et al. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol 1995;50:83–90. Google Scholar

  • 11.

    Okamoto Y, Morishita J, Tsuboi K, Tonai T, Ueda N. Molecular characterization of a phospholipase D generating anandamide and its congeners. J Biol Chem 2004;279:5298–305. Google Scholar

  • 12.

    Bisogno T, Howell F, Williams G, Minassi A, Cascio MG, Ligresti A, et al. Cloning of the first sn1-DAG lipases points to the spatial and temporal regulation of endocannabinoid signaling in the brain. J Cell Biol 2003;163:463–8. Google Scholar

  • 13.

    Cravatt BF, Giang DK, Mayfield SP, Boger DL, Lerner RA, Gilula NB. Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature 1996;384:83–7. Google Scholar

  • 14.

    Karlsson M, Contreras JA, Hellman U, Tornqvist H, Holm C. cDNA cloning, tissue distribution, and identification of the catalytic triad of monoglyceride lipase. Evolutionary relationship to esterases, lysophospholipases, and haloperoxidases. J Biol Chem 1997;272:27218–23. Google Scholar

  • 15.

    Long JZ, Li W, Booker L, Burston JJ, Kinsey SG, Schlosburg JE, et al. Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects. Nat Chem Biol 2009;5:37–44. Web of ScienceGoogle Scholar

  • 16.

    Seierstad M, Breitenbucher JG. Discovery and development of fatty acid amide hydrolase (FAAH) inhibitors. J Med Chem 2008;51:7327–43. Google Scholar

  • 17.

    Devane WA, Dysarz FA 3rd, Johnson MR, Melvin LS, Howlett AC. Determination and characterization of a cannabinoid receptor in rat brain. Mol Pharmacol 1988;34:605–13. Google Scholar

  • 18.

    Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 1990;346:561–4.Google Scholar

  • 19.

    Munro S, Thomas KL, Abu-Shaar M. Molecular characterization of a peripheral receptor for cannabinoids, Nature 1993;365:61–5. Google Scholar

  • 20.

    Tsou K, Brown S, Sañudo-Peña MC, Mackie K, Walker JM. Immunohistochemical distribution of cannabinoid CB1 receptors in the rat central nervous system, Neuroscience 1998;83:393–411.Google Scholar

  • 21.

    Buckley NE. The peripheral cannabinoid receptor knockout mice: an update. Br J Pharmacol 2008;153:309–18. Google Scholar

  • 22.

    Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, et al. International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev 2002;54:161–202. Google Scholar

  • 23.

    Begg M, Pacher P, Bátkai S, Osei-Hyiaman D, Offertáler L, Mo FM, et al. Evidence for novel cannabinoid receptors. Pharmacol Ther 2005;106:133–145. Google Scholar

  • 24.

    Ryberg E, Larsson N, Sjögren S, Hjorth S, Hermansson NO, Leonova J, et al. The orphan receptor GPR55 is a novel cannabinoid receptor. Br J Pharmacol 2007;152:1092–101. Google Scholar

  • 25.

    Sawzdargo M, Nguyen T, Lee DK, Lynch KR, Cheng R, Heng HHQ, et al. Identification and cloning of three novel human G protein-coupled receptor genes GPR52, PsiGPR53 and GPR55: GPR55 is extensively expressed in human brain. Mol Brain Res 1999;64:193–8. Google Scholar

  • 26.

    Henstridge CM, Balenga NA, Kargl J, Andradas C, Brown AJ, Irving A, et al. Minireview: recent developments in the physiology and pathology of the lysophosphatidylinositol-sensitive receptor GPR55. Mol Endocrinol 2011;25:1835–48. Web of ScienceGoogle Scholar

  • 27.

    Ross RA. L-α-lysophosphatidylinositol meets GPR55: a deadly relationship. Trends Pharmacol Sci 2011;32:265–9. Google Scholar

  • 28.

    Oka S, Toshida T, Maruyama K, Nakajima K, Yamashita A, Sugiura T. 2-Arachidonoyl-sn-glycero-3-phosphoinositol: a possible natural ligand for GPR55. J Biochem 2009;145:13–20. Web of ScienceGoogle Scholar

  • 29.

    Henstridge CM, Balenga NA, Ford LA, Ross RA, Waldhoer M, Irving AJ. The GPR55 ligand L-alpha-lysophosphatidylinositol promotes RhoA-dependent Ca2+ signaling and NFAT activation. FASEB J 2009;23:183–93. Google Scholar

  • 30.

    Rempel V, Volz N, Gläser F. Nieger M, Bräse S, Müller CE. Antagonists for the orphan G-protein-coupled receptor GPR55 based on a coumarin scaffold. J Med Chem 2013;56:4798–810. Web of ScienceGoogle Scholar

  • 31.

    Kotsikorou E, Lynch DL, Abood ME, Reggio PH. Lipid bilayer molecular dynamics study of lipid-derived agonists of the putative cannabinoid receptor, GPR55. Chem Phys Lipids 2011;164:131–43. Google Scholar

  • 32.

    Ross RA. The enigmatic pharmacology of GPR55. Trends Pharmacol Sci 2009;30:156–63.Google Scholar

  • 33.

    Henstridge CM, Balenga NA, Schröder R, Kargl JK, Platzer W, Martini L, et al. GPR55 ligands promote receptor coupling to multiple signalling pathways. Br J Pharmacol 2010;160: 604–14. Google Scholar

  • 34.

    Kapur A, Zhao P, Sharir H, Bai Y, Caron MG, Barak LS, et al. Atypical responsiveness of the orphan receptor GPR55 to cannabinoid ligands. J Biol Chem 2009;284:29817–27. Google Scholar

  • 35.

    Sharir H, Abood ME. Pharmacological characterization of GPR55, a putative cannabinoid receptor. Pharmacol Ther 2010;126:301–13. Google Scholar

  • 36.

    Kargl J, Balenga N, Parzmair GP, Brown AJ, Heinemann A, Waldhoer M. The cannabinoid receptor CB1 modulates the signaling properties of the lysophosphatidylinositol receptor GPR55. J Biol Chem 2012;287:44234–48. Google Scholar

  • 37.

    Moreno E, Andradas C, Medrano M, Caffarel MM, Pérez-Gómez E, Blasco-Benito S, et al. Targeting CB2-GPR55 receptor heteromers modulates cancer cell signaling. J Biol Chem 2014;289:21960–72. Google Scholar

  • 38.

    Balenga NA, Martínez-Pinilla E, Kargl J, Schröder R, Peinhaupt M, Platzer W, et al. Heteromerization of GPR55 and cannabinoid CB2 receptors modulates signalling. Br J Pharmacol 2014;171:5387–406. Google Scholar

  • 39.

    Schicho R, Storr M. A potential role for GPR55 in gastrointestinal functions. Curr Opin Pharmacol 2012;12:653–8. Google Scholar

  • 40.

    Li K, Fichna J, Schicho R, Saur D, Bashashati M, Mackie K, et al. A role for O-1602 and G protein-coupled receptor GPR55 in the control of colonic motility in mice. Neuropharmacology 2013;71:255–63.Web of ScienceGoogle Scholar

  • 41.

    Lin XH, Yuece B, Li YY, Feng YJ, Feng JY, Yu LY, et al. A novel CB receptor GPR55 and its ligands are involved in regulation of gut movement in rodents. Neurogastroenterol Motil 2011;23:862–e342. Web of ScienceGoogle Scholar

  • 42.

    Staton PC, Hatcher JP, Walker DJ, Morrison AD, Shapland EM, Hughes JP, et al. The putative cannabinoid receptor GPR55 plays a role in mechanical hyperalgesia associated with inflammatory and neuropathic pain. Pain 2008;139:225–36. Web of ScienceGoogle Scholar

  • 43.

    Balenga NA, Aflaki E, Kargl J, Platzer W, Schröder R, Blättermann S, et al. GPR55 regulates cannabinoid 2 receptor-mediated responses in human neutrophils. Cell Res 2011;21:1452–69. Web of ScienceGoogle Scholar

  • 44.

    Cantarella G, Scollo M, Lempereur L, Saccani-Jotti G, Basile F, Bernardini R. Endocannabinoids inhibit release of nerve growth factor by inflammation-activated mast cells. Biochem Pharmacol 2011;82:380–8. Web of ScienceGoogle Scholar

  • 45.

    Chiurchiù V, Lanuti M, De Bardi M, Battistini L, Maccarrone M. The differential characterization of GPR55 receptor in human peripheral blood reveals a distinctive expression in monocytes and NK cells and a proinflammatory role in these innate cells. Int Immunol 2015;27:153–60. Web of ScienceGoogle Scholar

  • 46.

    Borrelli F, Romano B, Petrosino S, Pagano E, Capasso R, Coppola D, et al. Palmitoylethanolamide, a naturally occurring lipid, is an orally effective intestinal anti-inflammatory agent. Br J Pharmacol 2015;172:142–58. Google Scholar

About the article

Corresponding author: Christian Lehmann, Department of Anesthesia, Pain Management and Perioperative Medicine, Dalhousie University, QE II Health Sciences Centre, 10 West Victoria, 1276 South Park Street, Halifax, Nova Scotia B3H 2Y9, Canada, Phone: +19024944454, E-mail: ; Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada; and Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada


Received: 2015-07-06

Accepted: 2015-10-18

Published Online: 2015-12-15

Published in Print: 2016-05-01


Citation Information: Journal of Basic and Clinical Physiology and Pharmacology, Volume 27, Issue 3, Pages 297–302, ISSN (Online) 2191-0286, ISSN (Print) 0792-6855, DOI: https://doi.org/10.1515/jbcpp-2015-0080.

Export Citation

©2016 by De Gruyter.Get Permission

Citing Articles

Here you can find all Crossref-listed publications in which this article is cited. If you would like to receive automatic email messages as soon as this article is cited in other publications, simply activate the “Citation Alert” on the top of this page.

[1]
Soraya Wilke Saliba, Hannah Jauch, Brahim Gargouri, Albrecht Keil, Thomas Hurrle, Nicole Volz, Florian Mohr, Mario van der Stelt, Stefan Bräse, and Bernd L. Fiebich
Journal of Neuroinflammation, 2018, Volume 15, Number 1
[2]
Silvia L. Cruz, Elizabeth Sánchez-Miranda, Jorge Ivan Castillo-Arellano, Rodolfo Daniel Cervantes-Villagrana, Alfredo Ibarra-Sánchez, and Claudia González-Espinosa
International Immunopharmacology, 2018, Volume 64, Page 298
[3]
Jeremy D Hill, Viviana Zuluaga-Ramirez, Sachin Gajghate, Malika Winfield, and Yuri Persidsky
British Journal of Pharmacology, 2018
[4]
Cristina Prandi, Marco Blangetti, Dvora Namdar, and Hinanit Koltai
Molecules, 2018, Volume 23, Number 7, Page 1526
[5]
Boris Castillo Chabeco, Gloria Figueroa, Tiyash Parira, Jacqueline Napuri, and Marisela Agudelo
Alcohol, 2018
[6]
Jonathan Gotfried, Rahul Kataria, and Ron Schey
Cannabis and Cannabinoid Research, 2017, Volume 2, Number 1, Page 252
[7]
Michael Delacher, Charles D Imbusch, Dieter Weichenhan, Achim Breiling, Agnes Hotz-Wagenblatt, Ulrike Träger, Ann-Cathrin Hofer, Danny Kägebein, Qi Wang, Felix Frauhammer, Jan-Philipp Mallm, Katharina Bauer, Carl Herrmann, Philipp A Lang, Benedikt Brors, Christoph Plass, and Markus Feuerer
Nature Immunology, 2017
[8]
Katrina Hurst, Corinne Badgley, Tanner Ellsworth, Spencer Bell, Lindsey Friend, Brad Prince, Jacob Welch, Zack Cowan, Ryan Williamson, Chris Lyon, Brandon Anderson, Brian Poole, Michael Christensen, Michael McNeil, Jarrod Call, and Jeffrey G. Edwards
Hippocampus, 2017, Volume 27, Number 9, Page 985
[9]
Melanie E. M. Kelly, Christian Lehmann, and Juan Zhou
Colloquium Series on Integrated Systems Physiology: From Molecule to Function, 2017, Volume 9, Number 2, Page i
[10]
Yan Lu and Hope D. Anderson
Canadian Journal of Physiology and Pharmacology, 2017, Volume 95, Number 4, Page 311
[11]
Joseph V. Pergolizzi, Robert Taylor, Jo Ann LeQuang, Gianpietro Zampogna, and Robert B. Raffa
Cancer Chemotherapy and Pharmacology, 2017, Volume 79, Number 3, Page 467
[12]
D Katz, I Katz, BS Porat-Katz, and Y Shoenfeld
Clinical Pharmacology & Therapeutics, 2017, Volume 101, Number 2, Page 230
[13]
Zachary Wilmer Reichenbach and Ron Schey
Current Treatment Options in Gastroenterology, 2016, Volume 14, Number 4, Page 461
[14]
Stefania Petrosino and Vincenzo Di Marzo
British Journal of Pharmacology, 2017, Volume 174, Number 11, Page 1349
[15]
Juan Zhou, Ian Burkovskiy, Hyewon Yang, Joel Sardinha, and Christian Lehmann
Frontiers in Pharmacology, 2016, Volume 7

Comments (0)

Please log in or register to comment.
Log in