GPR55
Synonyms
Historical Background
Snake plot diagram of the human GPR55 receptor. GPR55 is a seven transmembrane spanning receptor with an extracellular N-terminal domain and an intracellular C-terminal domain (Diagram generated by Protter (Omasits et al. 2013))
Amino acid sequence alignment of mouse (NP_001028462.2), rat (XP_006245556.1), and human (NP_005674.2) GPR55 genes. Blue boxes are transmembrane regions, and green shaded regions are amino acids conserved between all three receptors. Alignment performed by CLUSTAL Omega (1.2.2)
Following the characterization of the cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2), it was then postulated that there was a third or “atypical” cannabinoid receptor, “CBx.” This receptor is sensitive to both anandamide (AEA) and the “atypical” cannabinoid abnormal cannabidiol (Abn-CBD) in endothelial cells (Jarai et al. 1999; Wagner et al. 1999). This unknown receptor was found to mediate mesenteric vasodilation distinct from activation of CB1 and CB2 (Jarai et al. 1999; Wagner et al. 1999). It was then hypothesized that GPR55 may be the unknown cannabinoid receptor, as GPR55 is sensitive to the “atypical” cannabinoids, and an in silico screen later indicated that GPR55 was a cannabinoid receptor (Baker et al. 2006). However, Johns et al. (2007) showed that the vasodilatory effects of Abn-CBD in the presence and absence of O-1918 (a nonspecific putative GPR55 antagonist) were similar in mesenteric vessels obtained from GPR55 knockout mice and wild-type mice, in addition to no difference in resting heart rate or blood pressure between these two mice strains. The authors also stated that a limitation of the study is that they did not determine the antagonistic effect of O-1918 on Abn-CBD-increased GTPγS activation in GPR55 transfected cells, which would have helped to further support the observations in the mice (Johns et al. 2007).
Amino acid sequence alignment of human CB1 (NP_001153698.1), CB2 (NP_001832.1), and GPR55 (NP_005674.2) genes. Blue boxes are transmembrane regions, and green shaded regions are amino acids conserved between all three receptors. Alignment performed by CLUSTAL Omega (1.2.2)
Regardless of whether GPR55 is classified as a cannabinoid receptor, emerging research over the past two decades has been undertaken to help understand this receptor’s physiological/pathophysiological role for pharmacological purposes.
GPR55 Tissue Expression
A comparison of GPR55 expression between mouse, rat, and human
| Organ/cell | Mouse | Rat | Human | |
|---|---|---|---|---|
| Central nervous system | + Cortex + Striatum + Hypothalamus + Hypothalamus + Hippocampus + Brain stem + Spinal cord | + Hippocampus + Thalamic nuclei + Midbrain Sawzdargo et al. (1999) | − Hippocampus − Thalamus − Cerebellum − Frontal cortex − Pons | |
| + Amygdala ++ Caudate nucleus + Cerebellum + Cingulate gyrus + Globus pallidus + Hippocampus + Hypothalamus + Locus coeruleus + Medial frontal gyrus | ++ Nucleus accumbens + Parahippocampal gyrus + Pituitary gland ++ Putamen + Spinal cord ++ Striatum + Substantia nigra + Superior frontal gyrus + Thalamus | |||
| + Medulla oblongata (− using Northern Blot; + using quantitative “real-time” PCR) | ||||
| Henstridge et al. (2011), Kremshofer et al. (2015), Oka et al. (2010), and Sawzdargo et al. (1999) | ||||
| Open image in new window | + Lung Ryberg et al. (2007) | + Trachea + Lung + Cartilage Henstridge et al. (2011, Kremshofer et al. (2015), and Oka et al. (2010) | ||
| Gastrointestinal tract | + Esophagus + Stomach + Jejunum + Ileum + Colon + Mucosa + Muscle layer | + Small intestine + Colon | + Salivary glands + Esophagus + Stomach ++ Small intestine + Colon Henstridge et al. (2011), Kremshofer et al. (2015), and Oka et al. (2010) | |
| Pancreas | + Pancreas McKillop et al. (2013) | + Pancreatic islets + β islets (protein) − α and δ islets (protein) + BRIN-BD11 cells | + Pancreas Henstridge et al. (2011) | |
| Liver | + Liver Ryberg et al. (2007) | + Liver Romero-Zerbo et al. (2011) | − /+ Liver (− Northern Blot; + quantitative “real-time” PCR) | |
| White adipose tissue (WAT) | + WAT (Ryberg et al. 2007) | + WAT (Romero-Zerbo et al. 2011) | + WAT + Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) ↑ GPR55 VAT and SAT in obesity ↑ GPR55 obese T2D VAT | |
| Renal system | + Kidney + Adrenal glands ++ Bladder Ryberg et al. (2007) | + Kidney Jenkin et al. (2010) | + HK2 proximal tubule cell line + Kidney + Adrenal glands + Bladder Jenkin et al. (2010), Kremshofer et al. (2015), Oka et al. (2010), and Henstridge et al. (2011) | |
| Open image in new window Heart, skeletal muscle, and endothelial cells | − Heart Ryberg et al. (2007) | + Heart + Skeletal muscle + Placental venous endothelial cell line EA.hy926 Henstridge et al. (2011); Kremshofer et al. (2015), and Waldeck-Weiermair et al. (2008) | ||
| Bone | + Osteoblasts (protein also) + Osteoclasts (proteins also) Whyte et al. (2009) | + Osteoblasts (protein also) + Osteoclasts (protein also) + Bone + Bone marrow | ||
| White blood cells and platelets | + Peripheral blood Mononuclear cells + Macrophages + CD+T cells + B cells ++ Natural killer cells ++ Monocytes + Platelets | |||
| Male reproductive system | ++ Testes + Prostate Henstridge et al. (2011), Kremshofer et al. (2015), and Oka et al. 2010) | |||
| Female reproductive system | ++ Uterus Ryberg et al. (2007) | + Fetal tissues Sawzdargo et al. (1999) | + Cervix + Uterus + Human placenta ↑ mRNA full-term compared to first trimester placenta Henstridge et al. (2011), Kremshofer et al. (2015), and Oka et al. (2010) | |
| Open image in new window Thymus, spleen, and thyroid gland | + Spleen Ryberg et al. (2007) | + Spleen | ++ Spleen + Thyroid gland ++ Thymus Henstridge et al. (2011), Kremshofer et al. (2015), and Oka et al. (2010) | |
Pharmacology
The pharmacology of GPR55 is quite complex as there have been conflicting findings surrounding this receptor and some of its cannabinoid ligands (Kapur et al. 2009; Lauckner et al. 2008; Oka et al. 2007; Ryberg et al. 2007; Waldeck-Weiermair et al. 2008). This is likely due to a number of reasons including a number of fatty acid- and plant-derived compounds which are not specifically selective to GPR55 and thus have off-target effects. For example, oleoylethanolamide (OEA) is an agonist for both GPR55 and G protein-coupled receptor 119 (Ryberg et al. 2007; Overton et al. 2008). Additionally, research has focused on a number of different cell lines/types and different assays which have been utilized to determine agonist and antagonist binding and signaling properties (Kapur et al. 2009; Lauckner et al. 2008; Oka et al. 2007; Ryberg et al. 2007; Waldeck-Weiermair et al. 2008). Therefore, variability in the experimental design could also add to these conflicting results (Pertwee et al. 2010), as well as the possibility of biased signaling (Henstridge et al. 2010). To add to the complexity surrounding GPR55 pharmacology, GPR55 signaling can also be influenced by the two cannabinoid receptors CB1 and CB2, as GPR55 forms heteromers with these GPCRs (Balenga et al. 2014; Kargl et al. 2012; Martinez-Pinilla et al. 2014), which will be discussed in more detail in the GPR55 signaling pathways section.
Ligands for GPR55
| Compound | Compound type | Some of the observed actions at GPR55 |
|---|---|---|
| L-α-lysophosphatidylinositol (LPI) | Endogenous fatty acid | Agonist (Henstridge et al. 2009, Henstridge et al. 2010, Oka et al. 2007) • Increases GTPγS binding (Oka et al. 2007), ERK1/2 phosphorylation (Oka et al. 2007), and Ca2+ mobilization (Henstridge et al. 2009; Lauckner et al. 2008; Oka et al. 2007) in HEK293 cells transfected with human GPR55 (hGPR55) • Increases RhoA activation in both human and mouse osteoclast primary cells (Whyte et al. 2009) • Mediates ERK1/2 phosphorylation, β-arrestin activation, and GPR55 internalization in U2OS cells expressing GPR55 (Kapur et al. 2009) |
| Anandamide (AEA) | Endogenous fatty acid – endocannabinoid | Agonist (Lauckner et al. 2008; Ryberg et al. 2007; Waldeck-Weiermair et al. 2008) Inconsistent findings depending on the functional assay and cells used • Increases [35S] GTPγS binding, RhoA activation (Ryberg et al. 2007), and Ca2+ mobilization (Lauckner et al. 2008) in HEK293 cells transfected with (hGPR55) • Increases ERK1/2 phosphorylation in EA.hy926 cells (Waldeck-Weiermair et al. 2008) • No effect on ERK1/2 phosphorylation, β-arrestin activation, or GPR55 internalization in U2OS cells expressing GPR55 (Kapur et al. 2009) |
| 2-Arachidonoylglycerol (2-AG) | Endogenous fatty acid – endocannabinoid | Agonist (Ryberg et al. 2007) Inconsistent findings depending on functional assay and cells type used • Increases [35S] GTPγS binding in HEK293 cells transfected with hGPR55 (Ryberg et al. 2007) • No effect in HEK293 cells transfected with hGPR55 for Ca2+ mobilization and ERK1/2 phosphorylation (Oka et al. 2007) • No effect on Ca2+ mobilization in dorsal root ganglion derived from mice (Lauckner et al. 2008) • No effect on ERK1/2 phosphorylation, β-arrestin activation, or GPR55 internalization in U2OS cells expressing GPR55 (Kapur et al. 2009) |
| Noladin ether | Endogenous fatty acid – endocannabinoid | Agonist (Ryberg et al. 2007) • Increases [35S] GTPγS binding in HEK293 cells transfected with hGPR55 (Ryberg et al. 2007) |
| Oleoylethanolamide (OEA) | Endogenous fatty acid | Agonist (Ryberg et al. 2007) • Increases [35S] GTPγS binding in HEK293 cells transfected with hGPR55 (Ryberg et al. 2007) |
| Palmitoylethanolamide (PEA) | Endogenous fatty acid | Agonist (Ryberg et al. 2007) Inconsistent findings depending on functional assay and cells type used • Increases [35S] GTPγS binding in HEK293 cells transfected with hGPR55 (Ryberg et al. 2007) • No effect on β-arrestin activation in U2OS cells expressing GPR55 (Kapur et al. 2009) |
| Δ9Tetrahydrocannabinol (Δ9THC) | Cannabis sativa plant derivative | Agonist (Ryberg et al. 2007) Inconsistent findings depending on functional assay and cells type used. • Increases [35S] GTPγS binding in HEK293 cells transfected with hGPR55 (Ryberg et al. 2007) • Stimulates Ca2+ mobilization and RhoA activation in hGPR55-transfected HEK293 cells (Lauckner et al. 2008) • Stimulates Ca2+ hGPR55-transfected HEK293 cells (Lauckner et al. 2008) • No effect on β-arrestin activation or GPR55 internalization in U2OS cells expressing GPR55 (Kapur et al. 2009) |
| Cannabidiol (CBD) | Cannabis sativa plant derivative | Antagonist (Ryberg et al. 2007; Whyte et al. 2009) • Inhibits agonist on [35S] GTPγS binding in HEK293 cells transfected with hGPR55 (Ryberg et al. 2007) • Antagonizes the effect that LPI had on ERK1/2 phosphorylation in human osteoclasts cells (Whyte et al. 2009) • No effect on β-arrestin activation in U2OS cells expressing GPR55 (Kapur et al. 2009) |
| Abnormal cannabidiol (Abn-CBD) | Synthetic regioisomer of CBD | Agonist (Ryberg et al. 2007) • Increases [35S] GTPγS binding in HEK293 cells transfected with hGPR55 (Ryberg et al. 2007) • No effect on Ca2+ mobilization in HEK293 cells transfected with hGPR55 (Oka et al. 2007) • No effect on β-arrestin activation in U2OS cells expressing GPR55 (Kapur et al. 2009) |
| O-1602 | Synthetic derivative of Abn-CBD | Agonist (Johns et al. 2007; Ryberg et al. 2007; Waldeck-Weiermair et al. 2008) • Increases [35S] GTPγS binding in HEK293 cells transfected with hGPR55 (Ryberg et al. 2007) • Increases ERK1/2 phosphorylation and RhoA activation in human osteoclasts cells (Whyte et al. 2009) • Initiates RhoA activation in mouse osteoclast cells (Whyte et al. 2009) • No effect on β-arrestin activation in U2OS cells expressing GPR55 (Kapur et al. 2009) |
| O-1918 | Synthetic derivative of CBD | Putative GPR55 antagonist (Henstridge et al. 2011; Kremshofer et al. 2015) • Structurally similar to CBD; however, no studies show that this compound actually binds to GPR55 • No effect on β-arrestin activation in U2OS cells expressing GPR55 (Kapur et al. 2009) |
| SR141716A (rimonabant) | Synthetic cannabinoid – diarylpyrazole | Agonist at higher μM concentrations and antagonist at lower μM concentrations • Antagonizes a number of GPR55 agonists in HEK293 cells transfected with hGPR55 and dorsal root ganglion from mice (Lauckner et al. 2008) • Increases β-arrestin activation and receptor internalization in U2OS cells expressing GPR55 (Kapur et al. 2009) |
| AM251 | Synthetic cannabinoid – diarylpyrazole | Agonist (Henstridge et al. 2010; Ryberg et al. 2007) • Increases [35S] GTPγS binding in HEK293 cells transfected with hGPR55 (Ryberg et al. 2007) • Induces β-arrestin activation and receptor internalization in U2OS cells expressing GPR55 (Kapur et al. 2009) |
| AM281 | Synthetic cannabinoid | Weak agonist (Henstridge et al. 2010) • No effect on [35S] GTPγS binding in HEK293 cells transfected with hGPR55 (Ryberg et al. 2007) • No effect β-arrestin activation and receptor internalization in U2OS cells expressing GPR55 (Kapur et al. 2009) |
| JWH-015 | Synthetic cannabinoid | Agonist (Ryberg et al. 2007) • Stimulates Ca2+ mobilization in hGPR55-transfected HEK293 cells and dorsal root ganglion derived from mice (Lauckner et al. 2008) • No effect on β-arrestin activation in U2OS cells expressing GPR55 (Kapur et al. 2009) |
| HU-210 | Synthetic cannabinoid | Agonist (Lauckner et al. 2008; Ryberg et al. 2007) • Increases [35S] GTPγS binding in HEK293 cells transfected with hGPR55 (Ryberg et al. 2007) • No effect on β-arrestin activation in U2OS cells expressing GPR55 (Kapur et al. 2009) |
| Virodhamine | Synthetic cannabinoid | Agonist • Increases [35S] GTPγS binding in HEK293 cells transfected with hGPR55 (Ryberg et al. 2007) |
| CP55940 | Synthetic cannabinoid | Agonist at lower concentrations and antagonist at high concentrations • Increases [35S] GTPγS binding in HEK293 cells transfected with hGPR55 (Ryberg et al. 2007) • Blocks formation of β-arrestin, receptor internalization, and phosphorylation of ERK1/2 in U2OS cells expressing GPR55 (Kapur et al. 2009) |
| GSK494581A | Synthetic | Selective agonist (Kargl et al. 2012) |
| GSK319197A | Synthetic | Selective agonist (Kargl et al. 2012) |
| CID1792197 | Synthetic | Selective agonist (Kotsikorou et al. 2011) |
| CID1172084 | Synthetic | Selective agonist (Kotsikorou et al. 2011) |
| CID2440433 | Synthetic | Selective agonist (Kotsikorou et al. 2011) |
| CID23612552 (ML191) | Synthetic | Selective antagonist (Kotsikorou et al. 2013) |
| CID1434953 (ML192) | Synthetic | Selective antagonist (Kotsikorou et al. 2013) |
| CID1261822 (ML193) | Synthetic | Selective antagonist (Kotsikorou et al. 2013) |
| CID16020046 | Synthetic | Selective antagonist (Kargl et al. 2013) |
GPR55 Signaling Pathways
GPR55 cellular signaling. Activation of GPR55 can initiate Gα12/13 (Henstridge et al. 2009; Lauckner et al. 2008; Ryberg et al. 2007) and Gαq subunits (Lauckner et al. 2008; Pertwee et al. 2010). The Gα12/13 subunit stimulates the RhoA (Henstridge et al. 2009; Lauckner et al. 2008; Ryberg et al. 2007). Activation of the RhoA-ROCK pathway increases the phosphorylation of p38 MAPK and then subsequently phosphorylation of ATF-2 (Oka et al. 2010). The initiation of the RhoA-ROCK pathway also results in activation of PLC, resulting in Ca2+ release from the endoplasmic reticulum triggering activation of transcription factor NFAT, resulting in nuclear translocation (Henstridge et al. 2009). Whereas the Gαq-mediated PLC activation results in the release of DAG and Ca2+ (Lauckner et al. 2008), which activates PKC and ERK1/2 phosphorylation, triggering CREB and NF-ĸβ (Henstridge et al. 2010). As a result, activation of the transcription factors ATF-2, NFAT, CREB, and NF-ĸβ may regulate gene expression within the nucleus of the cell (Henstridge et al. 2009, 2010; Lauckner et al. 2008; Oka et al. 2010; Ryberg et al. 2007; Whyte et al. 2009).
GPCRs can act not only as monomers but also as heteroreceptor complexes, which can impact on activation of receptor signaling pathways. GPR55 forms heteromers with both CB1 and CB2 (Balenga et al. 2011; Kargl et al. 2012; Martinez-Pinilla et al. 2014). In vitro experiments indicate that both GPR55 and CB1 form heteromers in HEK293 cell lines when both receptors are expressed (Kargl et al. 2012). Co-immunoprecipitation experiments show that HEK-CB1-GPR55 cells interact when compared with HEK293 cells singly expressing either CB1 or GPR55, Although, unstimulated CB1 and GPR55 do not appear to co-internalize (Kargl et al. 2012). Using a range of different agonists, it has been determined that in the presence of CB1, GPR55-mediated signaling is reduced or inhibited, and furthermore, CB1-mediated ERK1/2 and NFAT activation are enhanced in the presence of GPR55, and blocking CB1 inhibits GPR55 signaling (Kargl et al. 2012). Supporting these findings, another study used bioluminescence resonance energy transfer (BRET) and proximity ligation assay (PLA) which showed a direct interaction between CB1 and GPR55 and the formation of heteromers in HEK293 cells transiently co-transfected with human CB1 and GPR55 (Martinez-Pinilla et al. 2014). The same study also found that in vivo GPR55 and CB1 are co-expressed in rat and monkey striatum and these receptors also form heteromers in these tissues (Martinez-Pinilla et al. 2014).
In vitro experiments also indicate that both GPR55 and CB2 form heteromers (Balenga et al. 2014). GPR55-mediated signaling is diminished in a number of downstream signaling pathways including the activation of NFAT, NF-κβ, and CREB, yet in contrast ERK1/2 MAPK activation was improved with the formation of a heteromers between GPR55 and CB2 (Balenga et al. 2014). CB2-mediated signaling was also altered in the presence of GPR55 (Balenga et al. 2014). CB2 and GPR55 are both expressed in human neutrophils, and when both receptors are activated, the signaling pathways RhoA and cdc42 are enhanced, while Rac2 signaling is diminished (Balenga et al. 2011). In cancer cells, GPR55 and CB2 also have been found to form heteromers resulting in unique signaling properties (Moreno et al. 2014).
Taken together, as GPR55 is expressed in a number of tissues where CB1 and CB2 are also expressed, these studies suggest there could be pharmacological implications for the GPR55 and CB1 or CB2 heteromers, as traditional signaling of each receptor is altered when heteromers are formed.
(Patho)physiological Role of GPR55
Summary of (patho)physiological roles for GPR55. This figure summarizes the physiological roles GPR55 plays in the bone, gastrointestinal tract, vasculature, and pancreas. This figure also highlights the pathophysiological role GPR55 plays in inflammation, cancer, inflammatory, and neuropathic pain, as well as obesity and T2D. ↑ increased, AEA anandamide, GPR55 G protein-coupled receptor 55, GI gastrointestinal, LPI L-α-lysophosphatidylinositol, SAT subcutaneous adipose tissue, T1D type 1 diabetes mellitus, T2D type 2 diabetes mellitus, VAT visceral adipose tissue
Bone
GPR55 has been demonstrated to be involved in regulating osteoclast formation and function in vitro. Activation of GPR55, using either LPI or O-1602, stimulates osteoclast polarization and reabsorption (Whyte et al. 2009). Male GPR55 knockout mice but not the female knockout mice have proportionally higher osteoclast numbers in long bones and impaired osteoclast function when compared to male and female wild-type mice, respectively (Whyte et al. 2009). The same study suggests that blocking GPR55 using CBD can inhibit bone resorption in vivo. Taken together these findings add to the hypothesis that blocking GPR55 may be beneficial for bone turnover and arthritic diseases (Whyte et al. 2009).
Gastrointestinal Tract
GPR55 is expressed throughout the gastrointestinal tract (Henstridge et al. 2011; Ryberg et al. 2007; Kremshofer et al. 2015) and is abundantly expressed in the small intestine (Ryberg et al. 2007; Kremshofer et al. 2015). This receptor has been located in mucosal scrapings (Schicho et al. 2011) and myenteric plexus (Schicho et al. 2011) in the rat colon. Activating GPR55 has been shown to slow gastrointestinal motility (Li et al. 2013b). GPR55 therefore may play a role in gastrointestinal function, specifically, in secretion and motility.
GPR55 has also been shown to be involved in gastroparesis in a type 1 diabetes mellitus model using Streptozotocin (STZ) mice (Lin et al. 2014). The expression of GPR55 is upregulated in the stomach in this condition, and treatment with the potent agonist LPI helps to protect against gastroparesis in these mice.
Inflammation
GPR55 may have a pro-inflammatory role in colitis. One study used two different experimentally induced models of colitis, either by administrating dextran sulfate sodium into the drinking water or by intrarectally applying trinitrobenzene sulfonic acid (Stancic et al. 2015). Antagonizing GPR55 using highly selective antagonist CID16020046 in both models had an anti-inflammatory affect by reducing pro-inflammatory cytokines (Stancic et al. 2015). When GPR55 was antagonized using CID16020046, this compound also interfered with macrophage and lymphocyte recruitment in the colon, thereby protecting against inflammation in the colon (Stancic et al. 2015). In addition to the pharmacological modulation, GPR55 knockout mice have a reduction in inflammatory scores when compared to wild-type mice (Stancic et al. 2015). In contrast, another study found that administrating O-1602, which acts as an agonist for GPR55, had anti-inflammatory properties and ameliorated experimentally induced colitis (Schicho et al. 2011). However, this anti-inflammatory effect was still apparent in GPR55 knockout mice, suggesting that this compound was targeting a putative cannabinoid receptor other than GPR55 (Schicho et al. 2011). Therefore the current evidence suggests that blocking GPR55 may be beneficial in the treatment of inflammatory bowel disease; however additional supporting studies are required before any conclusive decisions can be made.
GPR55 is highly expressed in monocytes and natural killer cells; activation of these cells by LPI results in secretion of pro-inflammatory cytokines (Chiurchiu et al. 2015). Conversely, in a cerulein-induced acute pancreatitis model, GPR55 expression is reduced with treatment of either O-1602 or CBD (an agonist and antagonist for GPR55), in which O-1602 treatment improved pathological changes (Li et al. 2013a). Taken together, these studies indicate GPR55 may be a potential target for inflammatory-related conditions in the future, which may vary depending on the associated condition.
Cancer
A large body of evidence demonstrates that GPR55 and the GPR55 potent agonist LPI have a role in cancer progression. Circulating LPI levels are increased in individuals with colon cancer when compared with healthy individuals (Kargl et al. 2016). Furthermore, GPR55 expression has been correlated with cancer aggressiveness. GPR55 expression and LPI have been associated with proliferation in a number of cancers including ovarian, prostate, breast, and glioblastoma while being involved in migration of breast cancer (Leyva-Illades and Demorrow 2013) and colon cancer (Kargl et al. 2016). Given that GPR55 has a role in cancer progression, it is not surprising that the receptor is expressed in a number of cancers and cancer cell lines including cholangiocarcinoma, breast cancer, prostate cancer cell lines, ovarian cancer cell lines, glioblastoma, human pancreatic ductal adenocarcinoma, human skin tumors and other squamous cell carcinomas, lymphoblastoid cell lines, human astrocytoma, melanoma, B lymphoblastoma, and lung cancer (for an in-depth review on GPR55 as an emerging target for cancer therapy, refer to Leyva-Illades and Demorrow (2013)).
GPR55 has a role in migration and metastasis in colon cancer using human colorectal carcinoma 116 (HCT116) cells as a colon cancer model (Kargl et al. 2016). One study found that migration of cancer cells was induced when the potent GPR55 agonist, LPI, was added to HCT116 cells overexpressing GPR55 and that this effect was blocked by GPR55 antagonists (Kargl et al. 2016). Furthermore, chemotactic assays showed that invasion and migration of cancer cells were both inhibited by the GPR55 antagonists CID16020046 and CBD (Kargl et al. 2016).
Inflammatory and Neuropathic Pain
GPR55 appears to have a role in nociception. GPR55 knockout mice are resistant to neuropathic and inflammatory pain (Staton et al. 2008), while the GPR55 agonist O-1602 has pronociceptive effects (Staton et al. 2008). Therefore it may be hypothesized that activating GPR55 has pronociceptive properties for neuropathic pain while blocking the receptor may have antinociceptive results.
Obesity
Moreno-Navarrete et al. (2012) found that GPR55 expression is increased in obesity, specifically in visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT), with circulating levels of LPI also increased in human obesity (Moreno-Navarrete et al. 2012). LPI has also been shown to increase lipogenic genes in a human adipose tissue cell culture model (Moreno-Navarrete et al. 2012). In contrast, deletion of GPR55 in mice was found to promote obesity as GPR55 knockout mice had significantly reduced voluntary physical activity which was associated with the mice also having increased adiposity and increased insulin resistance (Meadows et al. 2016). Interestingly, the food intake of the GPR55 knockout mice was not altered (Meadows et al. 2016).
Diabetes Mellitus
As GPR55 is expressed in the insulin-secreting β cells in the islets of Langerhans, this suggests that this receptor has a role in insulin secretion (Romero-Zerbo et al. 2011). Romero-Zerbo et al. (2011) demonstrated that activating GPR55 using O-1602, in lean rats under hyperglycemic conditions, causes an improvement in glucose-stimulated insulin secretion. This effect was not evident in GPR55 knockout mice, supporting this receptor’s role in blood glucose regulation (Romero-Zerbo et al. 2011). Further, this study also demonstrated that acute administration of O-1602, in Wistar rats, caused an increase in glucose tolerance accompanied by an increase in plasma insulin levels (Romero-Zerbo et al. 2011). These findings are further supported by more recent work using a number of cannabinoid agonists known to activate GPR55, which increased insulin secretion in BRIN-BD11 cells (a glucose-sensing and insulin-secreting line derived from isolated rat pancreatic β cells) (McKillop et al. 2013).
Co-localization experiments from the same study also showed that GPR55 is co-localized with insulin in both BRIN-BD11 and pancreatic islets from mice, while there was no evidence of GPR55 in the α islets that secrete glucagon (McKillop et al. 2013). These findings further support the study by Romero-Zerbo et al. (2011) which found that mRNA and protein expression of GPR55 are expressed in β islets but not in the α or δ islets in rats. Taken together, these two studies support the hypothesis that activating GPR55 in β islets of the pancreas may enhance β cell function and could therefore be a beneficial therapeutic target in the treatment of diabetes mellitus.
Summary
Since the discovery of GPR55 in 1999, almost two decades of research has found that this receptor is diversely expressed throughout the human body. GPR55 has a number of different ligands, some of which are cannabinoid compounds and derivatives, with the non-cannabinoid endogenous fatty acid LPI being the most potent agonist for this receptor. GPR55 is a putative cannabinoid receptor which has a number of physiological roles in the bone, gastrointestinal tract, pancreas, and vasculature. Targeting this receptor may also be of benefit in inflammatory conditions, diabetes mellitus, inflammatory and neuropathic pain, cancer, and obesity. Signaling properties of GPR55 vary depending on the agonist/antagonist utilized. This receptor has also been found to form heteromers with both cannabinoid receptors CB1 and CB2. The receptors’ ability to form heteromers alters signaling properties of the receptors involved and thus may be leading to some variation in the literature regarding the effects of GPR55 in various tissues and pathophysiological conditions. Future directions should focus on the effect that the second-generation GPR55 agonists and antagonists have in different disease states, as well as these compounds’ effects on signaling using both in vitro and in vivo models. Further investigation into this receptors role is required to elucidate the therapeutic potential of GPR55 in current known and newly identified pathophysiological conditions.
Notes
Acknowledgments
A.C. Simcocks was supported by Australian Rotary Health and the Rotary Club of Ballarat South.
D.S. Hutchinson is supported by a National Health and Medical Research Council of Australia Career Development Fellowship.
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