Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

GPR55

  • A. C. Simcocks
  • L. O’Keefe
  • D. H. Hryciw
  • M. L. Mathai
  • D. S. Hutchinson
  • Andrew J. McAinch
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101626

Synonyms

Historical Background

G protein-coupled receptor 55 (GPR55) was first cloned in 1999 and is a 319 amino acid seven transmembrane G protein-coupled receptor (GPCR) that is mapped to chromosome 2q37 (human) (Sawzdargo et al. 1999). It displays features common with other Family A GPCRs including a short extracellular N-terminal and C-terminal tail and contains two highly conserved extracellular cysteine residues that form disulfide bonds to help stabilize the receptor structure. Glycosylation sites in its N-terminus are present, while its intracellular loops and C-terminal tail have a number of potential phosphorylation sites. Orthologues for GPR55 have been found in a number of mammalian species including rat, mouse, dog, cow, chimpanzee, and human (Baker et al. 2006) (Figs. 1 and 2).
GPR55, Fig. 1

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))

GPR55, Fig. 2

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).

It has since been established that both GPR55 and G protein-coupled receptor 18 (GPR18) are sensitive to Abn-CBD (Johns et al. 2007; McHugh et al. 2010; Ryberg et al. 2007), as well as other cannabinoid compounds, and as such are both cannabinoid receptor candidates (McHugh et al. 2012; Ryberg et al. 2007), although GPR55 has a low homology (10–15%) when compared to the cannabinoid receptors CB1 and CB2 (Baker et al. 2006) (Figure 3). Additional research is required before a decision surrounding the classification of GPR55 as a cannabinoid receptor can be made by the International Union of Basic and Clinical Pharmacology (IUPHAR) Committee as well as the Drug Class Subcommitee (Pertwee et al. 2010). One area of concern is that the pharmacological profile of this receptor remains controversial, with the receptor’s affinity to several cannabinoid ligands providing inconsistent results (Henstridge et al. 2010; Kapur et al. 2009; Pertwee et al. 2010).
GPR55, Fig. 3

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

GPR55 receptor expression has been demonstrated both peripherally and centrally in human, mouse, and rat with some similarities and differences in the distribution between species. Receptor expression has primarily been assessed through the measurement of mRNA levels (Table 1).
GPR55, Table 1

A comparison of GPR55 expression between mouse, rat, and human

Organ/cell

Mouse

Rat

Human

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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 Respiratory system

+ Lung

Ryberg et al. (2007)

 

+ Trachea

+ Lung

+ Cartilage

Henstridge et al. (2011, Kremshofer et al. (2015), and Oka et al. (2010)

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Gastrointestinal tract

+ Esophagus

+ Stomach

+ Jejunum

+ Ileum

+ Colon

+ Mucosa

+ Muscle layer

Ryberg et al. (2007 and Schicho et al. (2011)

+ Small intestine

+ Colon

Sawzdargo et al. (1999) and Lin et al. (2011)

+ Salivary glands

+ Esophagus

+ Stomach

++ Small intestine

+ Colon

Henstridge et al. (2011), Kremshofer et al. (2015), and Oka et al. (2010)

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Pancreas

+ Pancreas

McKillop et al. (2013)

+ Pancreatic islets

+ β islets (protein)

α and δ islets (protein)

+ BRIN-BD11 cells

McKillop et al. (2013 and Romero-Zerbo et al. (2011)

+ Pancreas

Henstridge et al. (2011)

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Liver

+ Liver

Ryberg et al. (2007)

+ Liver

Romero-Zerbo et al. (2011)

− /+ Liver ( Northern Blot; + quantitative “real-time” PCR)

Henstridge et al. (2011) and Sawzdargo et al. (1999)

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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

Henstridge et al. (2011) and Moreno-Navarrete et al. (2012)

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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)

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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)

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Bone

+ Osteoblasts (protein also)

+ Osteoclasts (proteins also)

Whyte et al. (2009)

 

+ Osteoblasts (protein also)

+ Osteoclasts (protein also)

+ Bone

+ Bone marrow

Henstridge et al. (2011) and Whyte et al. (2009)

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White blood cells and platelets

  

+ Peripheral blood Mononuclear cells

+ Macrophages

+ CD+T cells

+ B cells

++ Natural killer cells

++ Monocytes

+ Platelets

Chiurchiu et al. (2015) and Henstridge et al. (2011)

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Male reproductive system

  

++ Testes

+ Prostate

Henstridge et al. (2011), Kremshofer et al. (2015), and Oka et al. 2010)

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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)

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Thymus, spleen, and thyroid gland

+ Spleen

Ryberg et al. (2007)

+ Spleen

Romero-Zerbo et al. (2011) and Sawzdargo et al. (1999)

++ Spleen

+ Thyroid gland

++ Thymus

Henstridge et al. (2011), Kremshofer et al. (2015), and Oka et al. (2010)

This table highlights the expression of GPR55 in tissues or cells across three species including mouse, rat, and human

+ Indicates mRNA expression for GPR55 in tissue or cell (protein is specified if analyzed). Caution is advised when interpreting protein results, as GPCR antibodies tend to lack selectivity

++ Indicates abundant mRNA expression for GPR55 in tissue or cell

− Indicates no evidence of receptor expression for GPR55 in tissue

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.

A number of different ligands act as agonists and antagonists for GPR55, these include plant-derived, fatty acid-derived, and chemically synthesized compounds (Ryberg et al. 2007). A summary of these compounds are included in Table 2. Synthetic cannabinoid derivatives of plant-derived cannabidiol (CBD), including Abn-CBD and O-1602, have been shown to act as agonists for GPR55 (Ryberg et al. 2007; Whyte et al. 2009), whereas CBD acts as an antagonist (Ryberg et al. 2007). The CBD analog, O-1918, is thought to be an antagonist for the CBx receptor (Pertwee et al. 2010) as well as a putative GPR55 antagonist (Henstridge et al. 2011; Kremshofer et al. 2015), although there is no evidence for binding of O-1918 to GPR55 and further research into this is required. These atypical cannabinoid compounds have previously been used to help elucidate the role of GPR55 in human (patho)physiology (Li et al. 2013b; Whyte et al. 2009). However, some conflicting findings have been observed in GPR55 knockout mice (Johns et al. 2007; Schicho et al. 2011). It was established that Abn-CBD, O-1602, and CBD also have an affinity toward GPR18 (McHugh et al. 2012). Further research using the new-generation agonists and antagonists (Table 2), with the support of GPR55 knockout models, is required to provide further understanding surrounding the (patho)physiological role of GPR55.
GPR55, Table 2

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)

This table highlights the endogenous fatty acids, plant derivatives and synthetic compounds which act as agonist or antagonists for GPR55

GPR55 Signaling Pathways

A number of studies investigating the signaling pathways activated by GPR55 have been conducted in HEK293 (human embryonic kidney 293) cells transfected with the hGPR55, as well as other cells such as human bone osteosarcoma (U2OS) cells expressing GPR55, mouse dorsal root ganglion primary cells, human and mouse osteoclast primary cells, and placental venous endothelial cells (EA.hy926 cells) (Henstridge et al. 2010; Kapur et al. 2009; Lauckner et al. 2008; Oka et al. 2010; Ryberg et al. 2007; Waldeck-Weiermair et al. 2008). GPR55 is coupled to Gα12/13 and/or Gαq (Pertwee et al. 2010). This subsequently leads to activation of a number of intracellular signaling pathways depending on the ligand utilized, including the Ras homolog gene family member RhoA-associated protein kinase (RhoA-ROCK) pathway, resulting in downstream signaling to p38 mitogen-activated protein kinase (p38MAPK) and activating transcription factor-2 (ATF-2) phosphorylation (Oka et al. 2010) and/or phosphoinositide phospholipase C (PLC), Ca2+ mobilization, and subsequently nuclear factor of activated T cells (NFAT) nuclear translocation (Henstridge et al. 2009). Additionally, activation of PLC causes increase in Ca2+ release from the endoplasmic reticulum, leading to initiation of protein kinase C (PKC) and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation. ERK1/2 activates cAMP response element-binding protein (CREB) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-ĸβ) (Henstridge et al. 2010). Stimulation of GPR55 can also result in β-arrestin activation and internalization of the receptor (Kapur et al. 2009) (Refer to Fig. 4 – GPR55 cellular signaling – for a detailed diagram).
GPR55, Fig. 4

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

GPR55 is distributed in a number of tissues throughout the human body, which suggests that this receptor may have a number of (patho)physiological roles. As described below, emerging research has shown this receptor has a role physiologically in the pancreas, gastrointestinal tract, vasculature, and bone. GPR55 has also been implicated in a number of pathophysiological conditions including cancer, neuropathic pain, inflammatory conditions, obesity, and diabetes (Fig. 5).
GPR55, Fig. 5

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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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • A. C. Simcocks
    • 1
  • L. O’Keefe
    • 1
  • D. H. Hryciw
    • 1
    • 2
  • M. L. Mathai
    • 1
    • 3
  • D. S. Hutchinson
    • 4
  • Andrew J. McAinch
    • 5
  1. 1.Centre for Chronic Diseases, College of Health and BiomedicineVictoria University, St Albans CampusMelbourneAustralia
  2. 2.School of Natural SciencesGriffith UniversityNathanAustralia
  3. 3.The Florey Institute for Neuroscience and Mental HealthThe University of MelbourneParkvilleAustralia
  4. 4.Drug Discovery Biology, Monash Institute of Pharmaceutical SciencesMonash UniversityParkvilleAustralia
  5. 5.Centre for Chronic Diseases, College of Health and Biomedicine, Australian Institute for Musculoskeletal ScienceVictoria University, St Albans CampusMelbourneAustralia