Nomenclature: GPR55

Family: Class A Orphans

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates. 

This receptor has a proposed ligand; see the Latest Pairings page for more information.

Contents

Gene and Protein Information
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 319 2q36.3 GPR55 G protein-coupled receptor 55 55
Mouse 7 328 1 C5 Gpr55 G protein-coupled receptor 55 54
Rat 7 296 9q35 Gpr55 G protein-coupled receptor 55 54
Previous and Unofficial Names
GPR55
G protein-coupled receptor 55
Gpr55_predicted
G protein-coupled receptor 55 (predicted)
G-protein coupled receptor 55
LOC227326
Gm218
Database Links
ChEMBL Target
Ensembl Gene
Entrez Gene
GPCRDB
GeneCards
GenitoUrinary Development Molecular Anatomy Project
HomoloGene
Human Protein Reference Database
InterPro
KEGG Gene
OMIM
PharmGKB Gene
PhosphoSitePlus
Protein Ontology (PRO)
RefSeq Nucleotide
RefSeq Protein
TreeFam
UniGene Hs.
UniProtKB
Wikipedia
Natural/Endogenous Ligand(s)
lysophosphatidylinositol
Comments: Proposed ligand, several publications
Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
2-arachidonoylglycerol Hs Agonist 8.52 pEC50 54
pEC50 8.52 (EC50 3x10-9 M) [54]
JWH015 Hs Agonist 8.4 pEC50 54
pEC50 8.4 (EC50 4x10-9 M) [54]
N-palmitoylethanolamine Hs Agonist 8.4 pEC50 54
pEC50 8.4 (EC50 4x10-9 M) [54]
O-1602 Hs Agonist 7.89 – 8.85 pEC50 26,48,54
pEC50 7.89 – 8.85 (EC50 1.3x10-8 – 1.4x10-9 M) [26,48,54]
CP55940 Hs Agonist 8.3 pEC50 5,54
pEC50 8.3 (EC50 5x10-9 M) [5,54]
GSK494581A Hs Agonist 8.19 pEC50 10
pEC50 8.19 (EC50 6.5x10-9 M) [10]
GSK575594A Hs Agonist 8.17 pEC50 10
pEC50 8.17 (EC50 6.8x10-9 M) [10]
Δ9-tetrahydrocannabinol Hs Agonist 8.1 pEC50 54
pEC50 8.1 (EC50 8x10-9 M) [54]
2-arachidonyl glyceryl ether Hs Agonist 8.0 pEC50 54
pEC50 8.0 (EC50 1x10-8 M) [54]
O-arachidonoyl ethanolamine Hs Agonist 7.92 pEC50 54
pEC50 7.92 (EC50 1.2x10-8 M) [54]
anandamide Hs Agonist 7.74 pEC50 54
pEC50 7.74 (EC50 1.8x10-8 M) [54]
HU-210 Hs Agonist 7.59 pEC50 54
pEC50 7.59 (EC50 2.6x10-8 M) [54]
AM251 Hs Agonist 7.41 pEC50 54
pEC50 7.41 (EC50 3.9x10-8 M) [54]
abnormal cannabidiol Hs Agonist 5.51 – 8.6 pEC50 27,54
pEC50 8.6 (EC50 2.5x10-9 M) [27]
pEC50 5.51 – 5.71 (EC50 1.944x10-6 – 3.102x10-6 M) [54]
CID1792197 Hs Agonist 6.92 – 6.96 pEC50 31
pEC50 6.92 – 6.96 (EC50 1.2x10-7 – 1.1x10-7 M) [31]
CID1172084 Hs Agonist 6.74 – 6.8 pEC50 31
pEC50 6.74 – 6.8 (EC50 1.8x10-7 – 1.59x10-7 M) [31]
CID2440433 Hs Agonist 6.57 – 6.6 pEC50 31
pEC50 6.57 – 6.6 (EC50 2.7x10-7 – 2.5x10-7 M) [31]
lysophosphatidylinositol Hs Agonist 5.5 – 7.31 pEC50 19,43,58
pEC50 5.5 – 7.31 (EC50 4.9x10-8 – 1x10-6 M) [19,43,58]
N-oleoylethanolamide Hs Agonist 6.25 – 6.5 pEC50 54
pEC50 6.25 – 6.5 (EC50 3.15x10-7 – 5.65x10-7 M) [54]
CP55,244 Hs Inverse agonist 8.3 pIC50 10
pIC50 8.3 [10]
T1117 Hs Agonist - - 14
[14]
[3H]rimonabant Hs Partial agonist - - 54
[54]
[3H]CP55940 Hs Agonist - - 54
[54]
Agonist Comments
Lysophosphatidylinositol elicited a rapid Ca2+ transient in GPR55-expressing HEK-293 cells, and stimulated the binding of GTPγS to the GPR55-expressing cell membranes [43]. The agonist also stimulated binding of [35S]GTPγS to cell membranes (pEC50 6.47) in breast cancer cell line MDA-MB-231. The pEC50 for LPI in HEK293 assay was 7.2 [10].

Expression studies and biological activity suggest that 2-Arachidonoyl-sn-glycero-3-phosphoinositol is the endogenous ligand of GPR55 [44]. 2-Arachidonoylglycerol, palmitoylethanolamide, virodhamine, O-1602, oleoylethanolamide and abnormal-cannabidiol are all proposed to be GPR55 selective agonists [46]. One study using a beta-arrestin PathHunter assay found that the putative cannabinoid receptor GPR55 responded strongly to AM251, rimonabant, and lysophosphatidylinositol, but not to other previously described agonists [64]. It appears that GPR55 has several signaling modalities and that, while anandamide can activate systems containing this receptor, GPR55 cannot yet be primarily designated a receptor for this endocannabinoid [11]. Mixed findings may be the product of biased agonism at GPR55 or may have resulted simply from the use of different assay end points and cell systems [48]. Biological activity of arachidonic acid-containing LPI species towards GPR55 was shown to be markedly higher than that of LPI species containing other fatty acyl groups, suggesting that 2-arachidonolyl LPI is the most likely natural ligand of GPR55 [45].

Molecular dynamics studies of the lipid-derived agonists of GPR55 show that LPI and 2-AGPI sit much higher in the bilayer than AEA, with inositol head groups that can at times be solvated completely by water, and that the acyl chain of LPI has reduced flexibility. Additionally both 2-AGPI and LPI can adopt a tilted head group orientation by hydrogen bonding to the phospholipid phosphate/glycerol groups or via intramolecular hydrogen bonding, which may provide a low enough profile in the lipid bilayer for LPI and 2-AGPI to enter GPR55 via the putative TMH6/7 entry port [30].

By modeling of the GPR55 activated state, the GPR55 binding conformations of three of the novel agonists obtained from high throughput screening (CID1792197, CID1172084, and CID2440433; PubChem Compound IDs), indicates the molecular shapes and electrostatic potential distributions of these agonists mimic those of LPI. The GPR55 binding site accommodates ligands that have inverted-L or T shapes with long, thin profiles that can fit vertically deep in the receptor binding pocket while their broad head regions occupy a horizontal binding pocket near the GPR55 extracellular loops [30].

The EC50 values calculated for agonists and antagonists of GPR55 vary dramatically with the assay employed, even within the same cell type. This indicates that coupling efficiency to downstream effector systems is selectively modulated by different ligands. Also, although diarylpyrazole compounds induce GPR55 activity, it was generally observed that much higher concentrations than are typically used for CB1 receptor antagonism, thus physiological effects of low nM concentrations of these agents are likely to reflect CB1 receptor blockade [19].

Lower affinity of GPR55 for CP55940, compared with CB1, may explain autoradiographic studies that show a lack of binding of this ligand to mouse brain after genetic deletion of CB1 [9]. Potency of all the agonists listed has been shown to vary dramatically between the assays employed for measurement [47].

GPR55-mediated actions of SR141716A; some reports indicate the compound to be an agonist and some report antagonism. This is because agonists alone and as inhibitors of LPI signaling under the same assay conditions. In contrast, CB2 ligand GW405833 behaves as a partial agonist of GPR55 alone and enhances LPI signaling. The phytocannabinoids Δ9-tetrahydrocannabivarin, cannabidivarin, and cannabigerovarin are also potent inhibitors of LPI, and may be novel therapeutic targets for GPR55 [2].

T1117 is a fluorescent form of AM251 [14]. GSK agonists are benzoylpiperazines originally identified as inhibitors of GlyT1. They activate human, but not rodent, GPR55 [10].

Biological activity of arachidonic acid-containing LPI species towards GPR55 was shown to be markedly higher than that of LPI species containing other fatty acyl groups, suggesting that 2-arachidonolyl LPI is the most likely natural ligand of GPR55 [45].
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
rimonabant Hs Antagonist 5.26 – 6.55 pEC50 10,19
pEC50 5.26 – 6.55 (EC50 2.8x10-7 – 5.5x10-6 M) [10,19]
AM281 Hs Antagonist 7.87 – 8.52 pIC50 19,54
pIC50 7.87 – 8.52 (IC50 3x10-9 – 1.36x10-8 M) [19,54]
CP55,667 Hs Inverse agonist 6.8 pIC50 10
pIC50 6.8 [10]
cannabidiol Hs Antagonist 6.35 – 6.46 pIC50 48,54
pIC50 6.35 – 6.46 (IC50 3.5x10-7 – 4.45x10-7 M) [48,54]
Primary Transduction Mechanisms
Transducer Effector/Response
Gq/G11 family
G12/G13 family
Phospholipase C stimulation
Other - See Comments
Comments:  GPR55 couples to Gα13 and can mediate activation of rhoA, cdc42 and rac1 [54]. However all other GPCRs known to activate G13 also activate other G proteins, so further G protein-signalling pathways for GPR55 may remain to be discovered [34]. Examination of its signaling pathway in HEK293 cells transiently expressing GPR55 found the calcium increase to involve Gq, G12, RhoA, actin, phospholipase C, and calcium release from IP3R-gated stores [9]. GOR promotes activation of a range of signalling pathways: Ca2+ release, ERK1/2 phosphorylation, NFAT-, CREB- and NF-κB-transcription, and receptor internalisation [19]. Agonist mediated down-regulation of GPR55 is mediated via GPCR Associated Sorting Protein-1 (GASP-1). Disrupting the GPR55-GASP-1 interaction prevents post-endocytic receptor degradation, and thereby allowed receptor recycling [21718301].
References:  54
Secondary Transduction Mechanisms
Transducer Effector/Response
Phospholipase C stimulation
Comments:  Under conditions of inactive integrins, anandamide initiates CB1 receptor-derived signaling, while Syk inhibits phosphoinositide 3-kinase representing a key protein in the transduction of GPR55-originated signaling. However, once integrins are clustered, CB1 receptor splits from integrins and, thus, Syk cannot further inhibit GPR55-triggered signaling resulting in intracellular Ca2+ mobilization from the endoplasmic reticulum (ER) via a PI3K-Bmx-phospholipase C (PLC) pathway and activation of nuclear factor of activated T-cells [61]. Agonist mediated down-regulation of GPR55 is mediated via GPCR Associated Sorting Protein-1 (GASP-1). Disrupting the GPR55-GASP-1 interaction prevents post-endocytic receptor degradation, and thereby allowed receptor recycling.
References:  28,61
Tissue Distribution
Spleen, thymus, small intestine, thymus, IM-9 cells
Expression level:  High
Species:  Human
Technique:  RT-PCR
References:  42
Cell lines: neutrophils, platelets, SA052
Expression level:  Medium
Species:  Human
Technique:  RT-PCR
References:  18
Cell lines: CCF-STTG1, HS-683, H4, Prostate-SMC, UT7-EPO, macrophages, HOS, C2AO4
Expression level:  Low
Species:  Human
Technique:  RT-PCR
References:  18
Liver, heart, kidney
Expression level:  Low
Species:  Human
Technique:  RT-PCR
References:  42
Amygdala, cingulate gyrus, globus pallidus, hippocampus, locus coerileus, medial frontal gyrus, medulla oblongata, parahippocampal gyrus, substantia nigra, superior frontal gyrus, thalamus, spinal cord
Expression level:  Low
Species:  Human
Technique:  RT-PCR
References:  18
Hypothalamus
Expression level:  Medium
Species:  Human
Technique:  RT-PCR
References:  18
Caudate nucleus, nucleus accumbens, putamen, striatum
Expression level:  High
Species:  Human
Technique:  RT-PCR
References:  18
Heart, liver, foetal liver, kidney, muscle, macrophages, pancreas, prostate, placenta, cartilage, bone
Expression level:  Low
Species:  Human
Technique:  RT-PCR
References:  18
Large dorsal root ganglion neurons
Species:  Human
Technique:  Immunohistochemistry
References:  34
Cell lines: NT-2 PRE, lymphocytes
Expression level:  High
Species:  Human
Technique:  RT-PCR
References:  18
Adipocytes of subcutaneous visceral tissue
Species:  Human
Technique:  RT-PCR
References:  39
Caudate nucleus, putamen (NOT expressed in: hippocampus, thalamus, pons, cerebellum, frontal cortex, liver)
Species:  Human
Technique:  Northen blot
References:  55
Osteoclasts and osteoblasts
Species:  Human
Technique:  Immunohistochemistry, qPCR
References:  62
Ovarian cancer cell lines (OVCAR3, A2780), prostate cancer cell lines (PC-3, DU145, LNCaP)
Species:  Human
Technique:  Western blot, immunohistochemistry, qPCR
References:  51
Brain, lung, colon
Expression level:  Medium
Species:  Human
Technique:  RT-PCR
References:  42
MDA-MB-231 breast cancer cell line
Species:  Human
Technique:  qRT-PCR
References:  16
Cancer cell lines
Species:  Human
Technique:  Immunocytochemistry
References:  3,22
Brain, pituitary, stomach, intestine, spleen, PBMC
Expression level:  High
Species:  Human
Technique:  RT-PCR
References:  18
Lung, bone marrow, adipose tissue
Expression level:  Medium
Species:  Human
Technique:  RT-PCR
References:  18
Adrenal, GI tract, CNS, brain
Species:  Mouse
Technique:  qPCR
References:  54
Schwann cells
Species:  Mouse
Technique:  Immunohistochemistry
References:  14
Microglia
Species:  Mouse
Technique:  qPCR
References:  50
Osteoclasts and osteoblasts
Species:  Mouse
Technique:  Immunohistochemistry, qPCR
References:  62
Cerebellar granule cells
Species:  Rat
Technique:  RT-PCR
References:  13
Submucosa and mesenteric plexus of gut
Species:  Rat
Technique:  Immunohistochemistry
References:  35
Islets of Langerhans (pancreatic β-cells)
Species:  Rat
Technique:  RT-qPCR, Western blot, double immunofluorescence
References:  52
Spleen, intestine, fetal tissues, hippocampus, thalamic nuclei, midbrain
Species:  Rat
Technique:  Northern blot; in situ hybridization
References:  55
Uterine NK cells, decidualised cells of the antimesometrial decidua (day 8 pregnancy), uterine maternal tissue: mesometrium, lateral zone, the glycogenic wing area, some decidualised cells, vascular smooth muscle (day 10 onwards), placenta (day 14).
Species:  Rat
Technique:  Immunohistochemistry
References:  15
Tissue Distribution Comments
GPR55 is expressed in adipose tissue and certain vascular beds [5]. LPS and IFN-γ reduce GPR55 mRNA expression in primary microglial cells [50]. Although GPR55 has been detected in the gut, it is not clear whether these receptors mediate the pharmacological effects of acylethanolamides [7]. GPR55 is present in brain tissue, with the necessary component for LPI signalling via this receptor [63]. GPR55 is expressed in human blood neutrophils [6]. PC12 cells (neural model cell line) express GPR55, predominantly localised on the plasma membrane in undifferentiated cells, and growth cones or ruffled border of differentiated cells [41].

Level of receptor expression in cancer cell lines was positively correlated with tumour grade (Elston-Ellis criteria), and proliferative index [4]. GPR55 is expressed in human cholangiocarcinoma cell lines and non-malignant H69 and HIBEC lines (RT-PCR and immunohistochemistry) [23]. Receptor expression in adipocytes of subcutaneous and visceral tissue is positively correlated with weight and BMI [39]. Acute withdrawal of alcohol causes reduced mRNA expression of cannabinoid receptors including orphan GPR55 in the amygdala. This downregulation is more pronounced with intermittent exposure to alcohol [57].
Expression Datasets

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Log average relative transcript abundance in mouse tissues measured by qPCR from Regard, J.B., Sato, I.T., and Coughlin, S.R. (2008). Anatomical profiling of G protein-coupled receptor expression. Cell, 135(3): 561-71. [PMID:18984166] [Raw data: website]

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Functional Assays
O-1602 and LPI inhibit mouse osteoclast formation in vitro, and stimulate mouse and human osteoclast polarization and resorption in vitro, causing activation of Rho and ERK1/2
Species:  Mouse
Tissue:  Osteoclasts
Response measured:  Polarisation and resorption
References:  62
LPI increases intracellular Ca2+ concentration, RhoA activity and ERK1/2 phosphorylation in PC12 cells via GPR55. It also causes neurite retraction in a Gα13 dependent manner
Species:  Human
Tissue:  PC12 neural cell line
Response measured:  Neurite retraction and actin redistribution
References:  41
O-1602 increases hind paw sensitisation in the chronic constriction injury model of neuropathic pain
Species:  Rat
Tissue:  Hindlimb nociceptors
Response measured:  Pronociceptive effect in neuropathic pain
References:  8
LPI is able to induce calcium mobilization and activation of Akt and ERK1/2 in prostate and ovarian cancer cell lines
Species:  Human
Tissue:  Ovarian and prostate cancer cell lines
Response measured:  Activation of LPI autocrine loop which increases cell proliferation
References:  51
LPI induces rapid phospohorylation of p38-mitogen-activated kinase in GPR55 expressing cells via the Rho-ROCK pathway
Species:  Human
Tissue:  HEK293 and IM-9 lymphoblastoid cells
Response measured:  Phosphorylation of p38 MAPK and time dependent phosphorylation of AFT-2
References:  42
LPI stimulates enhanced cell chemotaxis toward serum in metastatic cells
Species:  Human
Tissue:  MDA-MB-231 breast cancer cell line
Response measured:  Enhanced migration and invasive phenotype
References:  16
Activation of GPR55 by O-1602 decreases cell viability in malignant, but not non-malignant cholangiocyte cell lines in vitro and in xenograft tumours, due to recruitment of Fas death receptor into lipid rafts
Species:  Human
Tissue:  Cholangiocarcinoma and cholangiocyte cell lines
Response measured:  Increased apoptosis and decreased tumour growth
References:  23
LPI increases intracellular Ca2+ concentration in adipocytes via stimulation of GPR55. This increase is significantly higher in visceral adipose tissue compared to subcutaneous adipose tissue
Species:  Human
Tissue:  Adipocytes
Response measured:  Increased [Ca2+]i
References:  29
GPR55 inhibits M-type K+ current
Species:  Human
Tissue:  HEK-293 transfected cells
Response measured:  Patch clamp
References:  34
Treatment with LPI induced marked GPR55 internalization and stimulated a sustained, oscillatory Ca2+ release pathway, which was dependent on Gα13 and required RhoA activation
Species:  Human
Tissue:  HEK 293 cells
Response measured:  Activation of nuclear factor of activated T cells transcription factors and nuclear translocation
References:  17
O-1602 stimulation of GPR55 increases intracellular Ca2+ in rat pancreatic beta cells, increasing insulin secretion and peripheral glucose tolerance
Species:  Rat
Tissue:  Pancreas
Response measured:  Increased insulin secretion
References:  52
Functional Assay Comments
Activation of GPR55 augments the migratory response towards the CB2 receptor agonist 2-arachidonoylglycerol, while inhibiting neutrophil degranulation and reactive oxygen species production. In HEK293 and HL60 cell lines, and primary neutrophils, GPR55 and CB2 receptor interfere with each other's signaling pathways at the level of small GTPases, leading to cellular polarization and efficient migration as well as abrogation of degranulation and ROS formation in neutrophils [6].

The antiproliferative effects of GPR55 activation in cholangiocarcinoma require JNK activity and lipid rafts [23].
Physiological Functions
GPR55 mediates cell death in maternal uterine tissues
Species:  Rat
Tissue:  Decidual cells
References:  15
Stimulation of GPR55 by palmithoylethanolamide inhibits release of nerve growth factor by inflammation-activated mast cells, reducing endothelial cell proliferation and angiogenesis
Species:  Human
Tissue:  Mast cell line HCM-1
References:  12
O-1602 can alter joint nociception in a rat model of acute joint inflammation by reducing movement-evoked firing of nociceptive C fibres
Species:  Rat
Tissue:  Knee joint C fibres
References:  56
Physiological Functions Comments
GPR55 may be involved in mediating antinociceptive effects, suggested by assays involving weak cannabinoid receptor agonists PEA and AM251 [40].
Physiological Consequences of Altering Gene Expression
Analysis of the long bones from GPR55-/- mice revealed increased numbers of morphologically inactive osteoclasts but a significant increase in the volume and thickness of trabecular bone and the presence of unresorbed cartilage
Species:  Mouse
Tissue:  Osteoclasts
Technique:  Gene knockouts
References:  4,24,62
Stimulatory effects on osteoclast function were attenuated in osteoclasts generated from GPR55-/- macrophages
Species:  Mouse
Tissue:  Osteoclasts
Technique:  Gene knockouts
References:  62
Knock-down of GPR55 partly inhibited pro-angiogenic factor N-arachidonoyl serine-induced signal transduction and endothelial functions
Species:  Human
Tissue:  Primary human dermal microvascular endothelial cells
Technique:  RNA intererence (RNAi)
References:  21,65
Baseline haemodynamics and haemodynamic response to abnormal cannabidiol, and vasodilatory responses to atypical cannabinoids, were not different between WT and GPR55 KO mice
Species:  Mouse
Tissue:  Mesenteric resistance artery
Technique:  Targeting in embryonic stem cells
References:  20,27
Inflammatory mechanical hyperalgesia was completely absent in GPR55-/- mice up to 14 days post-injection, with increased levels of IL-4, IL-10, IFNγ and GM-CSF.
Species:  Mouse
Tissue:  Nociceptors
Technique:  Targeting in embryonic stem cells
References:  60
When GPR55 was overexpressed in MCF-7 cells, a serum induced a robust migratory and invasive response, which was further enhanced by LPI due to marked cancer cell-polarization, and prevented by siRNA to GPR55.
Species:  Human
Tissue:  MCF-7 cells
Technique:  Gene over-expression
References:  16,22
Stable overexpression of GPR55 in HEK293 cells enhanced their proliferative potential and ERK phosphorylation. Increased cell viability was seen with overexpression of GPR55 in cancer cell lines
Species:  Human
Tissue:  HEK293, Breast cancer cells, T98G glioma cells and pancreatic adenocarcinoma MIA PaCa-2 cells
Technique:  Gene over expression
References:  3
SiRNA knockdown of GPR55 in Mz-ChA-1 cells inhibited the antiproliferative effect of GPR55 when activated by AEA and O-1602, and prevented the pro-apoptotic phenotype of the WT transfected cells
Species:  Human
Tissue:  Cholangiocarcinoma cell line
Technique:  Not specified
References:  23
siRNA knockdown of GPR55 in PC12 neural cells prevented LPI induced neurite retraction
Species:  Human
Tissue:  PC12 neural cell line
Technique:  RNA interference (RNAi)
References:  41
Physiological Consequences of Altering Gene Expression Comments
Leptin deficient mice and rats fed a high-fat diet display significantly reduced GPR55 mRNA and protein levels, suggesting differential regulation of GPR55 in rodents and humans [39].
Phenotypes, Alleles and Disease Models Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Gpr55tm1.1Mijr Gpr55tm1.1Mijr/Gpr55tm1.1Mijr
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:2685064  MP:0000130 abnormal cancellous bone morphology PMID: 19805329 
Gpr55tm1.1Mijr Gpr55tm1.1Mijr/Gpr55tm1.1Mijr
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:2685064  MP:0008396 abnormal osteoclast differentiation PMID: 19805329 
Gpr55tm1.1Mijr Gpr55tm1.1Mijr/Gpr55tm1.1Mijr
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:2685064  MP:0004982 abnormal osteoclast morphology PMID: 19805329 
Gpr55tm1.1Mijr Gpr55tm1.1Mijr/Gpr55tm1.1Mijr
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:2685064  MP:0001541 abnormal osteoclast physiology PMID: 19805329 
Gpr55tm1.1Mijr Gpr55tm1.1Mijr/Gpr55tm1.1Mijr
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:2685064  MP:0008872 abnormal physiological response to xenobiotic PMID: 19805329 
Gpr55tm1.1Mijr Gpr55tm1.1Mijr/Gpr55tm1.1Mijr
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:2685064  MP:0004985 decreased osteoclast cell number PMID: 19805329 
Gpr55tm1.1Mijr Gpr55tm1.1Mijr/Gpr55tm1.1Mijr
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:2685064  MP:0005605 increased bone mass PMID: 19805329 
Gpr55tm1.1Mijr Gpr55tm1.1Mijr/Gpr55tm1.1Mijr
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:2685064  MP:0004984 increased osteoclast cell number PMID: 19805329 
Gpr55tm1Lex Gpr55tm1Lex/Gpr55tm1Lex
involves: 129S/SvEvBrd * C57BL/6J
MGI:2685064  MP:0002169 no abnormal phenotype detected
Clinically-Relevant Mutations and Pathophysiology Comments
GPR55 has been proposed to have specific influences on cannabis use disorders [1]. Functional polymorphism rs3749073 (Gly195Val) in the GPR55 gene is associated with anorexia nervosa [25].
Gene Expression and Pathophysiology Comments
A role for GPR55 in mechanical hypersensitivity makes the receptor a novel target for analgesic therapy [33,59]. GPR55 has been shown to mediate anchorage dependent and independent cell proliferation in prostate cancer and ovarian cancer cell lines in vitro [51]. Expression of GPR55 in human tumours from different origins appears to correlate with degree of aggression [3].

GPR55 is upregulated in LPS-induced inflammatory responses, and activated in inflammatory bowel disease characterised by LPS-induced movement disorders (rodent model). This is inhibited by antagonists of the receptor [35].
Biologically Significant Variants
Type:  SNP
Species:  Human
Change:  G195V
Global MAF (%):  17
Subpopulation MAF (%):  AFR|AMR|ASN|EUR: 38|8|15|8
Minor allele count:  A=0.166/363
SNP accession: 
Validation:  1000 Genomes, HapMap, Frequency
Type:  SNP
Species:  Human
Change:  V103I
Global MAF (%):  2
Subpopulation MAF (%):  AFR|AMR: 10|1
Minor allele count:  T=0.024/53
SNP accession: 
Validation:  1000 Genomes, Frequency
Type:  SNP
Species:  Human
Change:  T215N
Global MAF (%):  1
Subpopulation MAF (%):  AFR: 3
Minor allele count:  T=0.006/14
Comment on frequency:  Low frequency (<10% in all tested populations)
SNP accession: 
Validation:  1000 Genomes, Frequency
General Comments
Patents lodged independently by GlaxoSmithKline (WO/2001/086305) and AstraZeneca (WO/2004/074844) in recent years claimed that the GPR55 receptor is activated by several CB1 and CB2 receptor ligands, prompting further research which supported this [54]. However, more recently Oka et al. [43] has refuted these claims and presented evidence that GPR55 is an intrinsic receptor for lysophosphatidylinositol (LPI). Further reports [17] and [44] support the findings of LPI activation and also demonstrate a certain sensitivity of GPR55 to a subset of cannabinoid ligands.

GPR55 may be a new cannabinoid receptor sensitive to CP55940; this analysis was made on the basis of sequence similarity between a number of GPR55 subdomains and the corresponding sequences of 'classic' cannabinoid receptors [49]. Although GPR55 shares only 14% similarity with CB1 and CB2, it may still express key amino acids that will allow its interaction with cannabinoid ligands [32]. Phylogenetic analysis of the endocannabinoid system suggests that functional GPR55 receptors are limited to mammals[37] . The endocannabinoid system is collectively under strong purifying selection, although some genes show evidence of adaptive evolution [38]. Zebrafish express no ortholog for GPR55 [36].

The established and unknown pharmacology of GPR55 is summarised in the review by Ross [53].
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To cite this database page, please use the following:

Anthony P. Davenport, Stephen Alexander, Joanna L. Sharman, Adam J. Pawson, Helen E. Benson, Amy E. Monaghan, Wen Chiy Liew, Chido Mpamhanga, Jim Battey, Richard V. Benya, Robert T. Jensen, Sadashiva Karnik, Evi Kostenis, Eliot Spindel, Laura Storjohann, Kalyan Tirupula, Tom I. Bonner, Richard Neubig, Jean-Philippe Pin, Michael Spedding, Anthony Harmar.
Class A Orphans: GPR55. Last modified on 07/02/2014. Accessed on 18/04/2014. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=109.

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