<i>GPR55</i> | GPR18, GPR55 and GPR119 | IUPHAR Guide to IMMUNOPHARMACOLOGY

GPR55

Immunopharmacology Ligand Target has curated data in GtoImmuPdb

Target id: 109

Nomenclature: GPR55

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

Gene and Protein Information
Database Links
Natural/Endogenous Ligands
Agonists
Antagonists
Immunopharmacology Comments
Immuno Cell Type Associations
Immuno Process Associations
Transduction Mechanisms
Tissue Distribution
Expression Datasets
Functional Assays
Physiological Functions
Physiological Consequences of Altering Gene Expression
Phenotypes, Alleles and Disease Models
Clinically-Relevant Mutations and Pathophysiology
Gene Expression and Pathophysiology
Biologically Significant Variants
General Comments
References
Contributors
How to cite this page

Gene and Protein Information
class A G protein-coupled receptor
Species	TM	AA	Chromosomal Location	Gene Symbol	Gene Name	Reference
Human	7	319	2q37.1	GPR55	G protein-coupled receptor 55	61
Mouse	7	327	1 C5	Gpr55	G protein-coupled receptor 55	60
Rat	7	296	9q35	Gpr55	G protein-coupled receptor 55	60

Database Links
Specialist databases
GPCRdb	gpr55_human (Hs), q9wu09_rat (Rn)
Other databases
Alphafold	Q9Y2T6 (Hs), Q3UJF0 (Mm), Q9WU09 (Rn)
ChEMBL Target	CHEMBL1075322 (Hs), CHEMBL4524044 (Rn)
Ensembl Gene	ENSG00000135898 (Hs), ENSMUSG00000049608 (Mm), ENSRNOG00000017521 (Rn)
Entrez Gene	9290 (Hs), 227326 (Mm), 501177 (Rn)
Human Protein Atlas	ENSG00000135898 (Hs)
KEGG Gene	hsa:9290 (Hs), mmu:227326 (Mm), rno:501177 (Rn)
OMIM	604107 (Hs)
Pharos	Q9Y2T6 (Hs)
RefSeq Nucleotide	NM_005683 (Hs), NM_001033290 (Mm)
RefSeq Protein	NP_005674 (Hs), NP_001028462 (Mm)
UniProtKB	Q9Y2T6 (Hs), Q3UJF0 (Mm), Q9WU09 (Rn)
Wikipedia	GPR55 (Hs)

Natural/Endogenous Ligands
anandamide
2-arachidonoylglycerol
2-arachidonoylglycerolphosphoinositol
lysophosphatidylinositol
N-palmitoylethanolamine
Comments: Proposed ligand, several publications

Download all structure-activity data for this target as a CSV file go icon to follow link

Agonists

Key to terms and symbols

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Ligand		Sp.	Action	Value	Parameter	Reference
2-arachidonoylglycerol		Hs	Agonist	8.5	pEC₅₀	60
⤷	pEC₅₀ 8.5 (EC₅₀ 3x10^-9 M) [60]
N-palmitoylethanolamine		Hs	Agonist	8.4	pEC₅₀	60
⤷	pEC₅₀ 8.4 (EC₅₀ 4x10^-9 M) [60]
JWH015		Hs	Agonist	8.4	pEC₅₀	60
⤷	pEC₅₀ 8.4 (EC₅₀ 4x10^-9 M) [60]
O-1602		Hs	Agonist	7.9 – 8.9	pEC₅₀	30,54,60
⤷	pEC₅₀ 7.9 – 8.9 (EC₅₀ 1.3x10^-8 – 1.4x10^-9 M) [30,54,60]
CP55940		Hs	Agonist	8.3	pEC₅₀	6,60
⤷	pEC₅₀ 8.3 (EC₅₀ 5x10^-9 M) [6,60]
GSK494581A		Hs	Agonist	8.2	pEC₅₀	11
⤷	pEC₅₀ 8.2 (EC₅₀ 6.5x10^-9 M) [11]
GSK575594A		Hs	Agonist	8.2	pEC₅₀	11
⤷	pEC₅₀ 8.2 (EC₅₀ 6.8x10^-9 M) [11]
Δ⁹-tetrahydrocannabinol		Hs	Agonist	8.1	pEC₅₀	60
⤷	pEC₅₀ 8.1 (EC₅₀ 8x10^-9 M) [60]
2-arachidonyl glyceryl ether		Hs	Agonist	8.0	pEC₅₀	60
⤷	pEC₅₀ 8.0 (EC₅₀ 1x10^-8 M) [60]
O-arachidonoyl ethanolamine		Hs	Agonist	7.9	pEC₅₀	60
⤷	pEC₅₀ 7.9 (EC₅₀ 1.2x10^-8 M) [60]
anandamide		Hs	Agonist	7.7	pEC₅₀	60
⤷	pEC₅₀ 7.7 (EC₅₀ 1.8x10^-8 M) [60]
HU-210		Hs	Agonist	7.6	pEC₅₀	60
⤷	pEC₅₀ 7.6 (EC₅₀ 2.6x10^-8 M) [60]
abnormal cannabidiol		Hs	Agonist	5.5 – 8.6	pEC₅₀	31,60
⤷	pEC₅₀ 8.6 (EC₅₀ 2.5x10^-9 M) [31] pEC₅₀ 5.5 – 5.7 (EC₅₀ 3.102x10^-6 – 1.944x10^-6 M) [60]
CID1792197		Hs	Agonist	6.9 – 7.0	pEC₅₀	37
⤷	pEC₅₀ 6.9 – 7.0 (EC₅₀ 1.2x10^-7 – 1.1x10^-7 M) [37]
CID1172084		Hs	Agonist	6.7 – 6.8	pEC₅₀	37
⤷	pEC₅₀ 6.7 – 6.8 (EC₅₀ 1.8x10^-7 – 1.59x10^-7 M) [37]
CLUL1 (52-77) {Sp: Human}		Hs	Agonist	6.7	pEC₅₀	18
⤷	pEC₅₀ 6.7 (EC₅₀ 1.82x10^-7 M) [18] Description: Determined in a dynamic mass redistribution (DMR) assay in Flp-In T-REx 293 cells expressing SNAP-tagged hGPR55.
MSMB (91-114) {Sp: Human}		Hs	Agonist	6.7	pEC₅₀	18
⤷	pEC₅₀ 6.7 (EC₅₀ 2.24x10^-7 M) [18] Description: Determined in a dynamic mass redistribution (DMR) assay in Flp-In T-REx 293 cells expressing SNAP-tagged hGPR55.
CID2440433		Hs	Agonist	6.6 – 6.6	pEC₅₀	37
⤷	pEC₅₀ 6.6 – 6.6 (EC₅₀ 2.7x10^-7 – 2.5x10^-7 M) [37]
lysophosphatidylinositol		Hs	Agonist	5.5 – 7.3	pEC₅₀	21,49,64
⤷	pEC₅₀ 5.5 – 7.3 (EC₅₀ 1x10^-6 – 4.9x10^-8 M) [21,49,64]
N-oleoylethanolamide		Hs	Agonist	6.3 – 6.5	pEC₅₀	60
⤷	pEC₅₀ 6.3 – 6.5 (EC₅₀ 5.65x10^-7 – 3.15x10^-7 M) [60]
AM251		Hs	Agonist	5.0 – 7.4	pEC₅₀	21,32,60
⤷	pEC₅₀ 5.0 – 7.4 (EC₅₀ 9.6x10^-6 – 3.9x10^-8 M) [21,32,60]
SPAG11B (61-103) {Sp: Human}		Hs	Agonist	5.7	pEC₅₀	18
⤷	pEC₅₀ 5.7 (EC₅₀ 2.042x10^-6 M) [18] Description: Determined in a real-time internalization TR-FRET assay in Flp-In T-REx 293 cells expressing SNAP-tagged hGPR55.
Chgb (511-532) {Sp: Rat}		Hs	Agonist	5.6	pEC₅₀
⤷	pEC₅₀ 5.6 (EC₅₀ 2.399x10^-6 M) Description: Determined in a dynamic mass redistribution (DMR) assay in Flp-In T-REx 293 cells expressing SNAP-tagged hGPR55.
MANSC (415-431) {Sp: Human}		Hs	Agonist	5.5	pEC₅₀	18
⤷	pEC₅₀ 5.5 (EC₅₀ 3.09x10^-6 M) [18] Description: Determined in a dynamic mass redistribution (DMR) assay in Flp-In T-REx 293 cells expressing SNAP-tagged hGPR55.
CP55,244		Hs	Inverse agonist	8.3	pIC₅₀	11
⤷	pIC₅₀ 8.3 [11]
[³H]CP55940		Hs	Agonist	-	-	60
⤷	[60]
[³H]rimonabant		Hs	Partial agonist	-	-	60
⤷	[60]
T1117		Hs	Agonist	-	-	15
⤷	[15]
compound 3a [Badolato et al., 2019]		Hs	Inverse agonist	-	-	5
⤷	[5]

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 [49]. 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 [11].

Expression studies and biological activity suggest that 2-Arachidonoyl-sn-glycero-3-phosphoinositol is the endogenous ligand of GPR55 [50]. 2-Arachidonoylglycerol, palmitoylethanolamide, virodhamine, O-1602, oleoylethanolamide and abnormal-cannabidiol are all proposed to be GPR55 selective agonists [52]. 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 [71]. 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 [12]. 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 [54]. 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 [51].

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 [36].

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 [36].

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 [21].

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 [10]. Potency of all the agonists listed has been shown to vary dramatically between the assays employed for measurement [53].

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 [15]. GSK agonists are benzoylpiperazines originally identified as inhibitors of GlyT1. They activate human, but not rodent, GPR55 [11].

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 [51].

Antagonists

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Ligand		Sp.	Action	Value	Parameter	Reference
CID16020046		Hs	Antagonist	7.3	pA₂	34
⤷	pA₂ 7.3 apparent pA₂ [34]
rimonabant		Hs	Antagonist	5.3 – 6.6	pEC₅₀	11,21
⤷	pEC₅₀ 5.3 – 6.6 (EC₅₀ 5.5x10^-6 – 2.8x10^-7 M) [11,21]
AM281		Hs	Antagonist	7.9 – 8.5	pIC₅₀	21,60
⤷	pIC₅₀ 7.9 – 8.5 (IC₅₀ 1.36x10^-8 – 3x10^-9 M) [21,60]
CP55,667		Hs	Inverse agonist	6.8	pIC₅₀	11
⤷	pIC₅₀ 6.8 [11]
ML193		Hs	Antagonist	6.7	pIC₅₀	22
⤷	pIC₅₀ 6.7 (IC₅₀ 2.21x10^-7 M) [22]
cannabidiol		Hs	Antagonist	6.3 – 6.5	pIC₅₀	54,60
⤷	pIC₅₀ 6.3 – 6.5 (IC₅₀ 4.45x10^-7 – 3.5x10^-7 M) [54,60]

Immunopharmacology Comments
Lysophosphatidylinositol (LPI)-activated GPR55 has been shown to negatively regulate migration to, and accumulation of γδ T cells (a type of intraepithelial lymphocytes or IELs) in the small intestine [66]. This action is dependent on GPR55 signalling via Gα₁₃. LPI is highly expressed in the gut and can inhibit IEL migration. Antagonism of GPR55 may be a novel mechanism that could improve immune surveillance of the epithelium and thereby protect from intestinal barrier dysfunction (e.g. NSAID-induced intestinal leakage or as associated with other types of intestinal disease).

Immunopharmacology Comments

Lysophosphatidylinositol (LPI)-activated GPR55 has been shown to negatively regulate migration to, and accumulation of γδ T cells (a type of intraepithelial lymphocytes or IELs) in the small intestine [66]. This action is dependent on GPR55 signalling via Gα₁₃. LPI is highly expressed in the gut and can inhibit IEL migration. Antagonism of GPR55 may be a novel mechanism that could improve immune surveillance of the epithelium and thereby protect from intestinal barrier dysfunction (e.g. NSAID-induced intestinal leakage or as associated with other types of intestinal disease).

Cell Type Associations

Immuno Cell Type:	Other T cells
Cell Ontology Term:	gamma-delta T cell (CL:0000798)
References:	66

Immuno Cell Type:	T cells
Cell Ontology Term:	CD4-positive, alpha-beta T cell (CL:0000624)
Comment:	GPR55 expression was detected in human immune cells by single cell RNA-sequencing, with expression being highest in CD4⁺ T cells.
References:	26

Immuno Process Associations

Immuno Process:

Immune regulation

Immuno Process:

Immune system development

Primary Transduction Mechanisms
Transducer	Effector/Response
G_q/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 [60]. 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 [40]. Examination of its signaling pathway in HEK293 cells transiently expressing GPR55 found the calcium increase to involve G_q, G₁₂, RhoA, actin, phospholipase C, and calcium release from IP₃R-gated stores [10]. GOR promotes activation of a range of signalling pathways: Ca²⁺ release, ERK_1/2 phosphorylation, NFAT-, CREB- and NF-κB-transcription, and receptor internalisation [21]. 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: 60

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 [68]. 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: 33,68

Tissue Distribution

Spleen, thymus, small intestine, thymus, IM-9 cells

Expression level:	High
Species:	Human
Technique:	RT-PCR
References:	48

Lung, bone marrow, adipose tissue

Expression level:	Medium
Species:	Human
Technique:	RT-PCR
References:	20

Cell lines: neutrophils, platelets, SA052

Expression level:	Medium
Species:	Human
Technique:	RT-PCR
References:	20

Adipocytes of subcutaneous visceral tissue

Species:	Human
Technique:	RT-PCR
References:	45

Caudate nucleus, putamen (NOT expressed in: hippocampus, thalamus, pons, cerebellum, frontal cortex, liver)

Species:	Human
Technique:	Northen blot
References:	61

Brain, pituitary, stomach, intestine, spleen, PBMC

Expression level:	High
Species:	Human
Technique:	RT-PCR
References:	20

Cell lines: CCF-STTG1, HS-683, H4, Prostate-SMC, UT7-EPO, macrophages, HOS, C2AO4

Expression level:	Low
Species:	Human
Technique:	RT-PCR
References:	20

Liver, heart, kidney

Expression level:	Low
Species:	Human
Technique:	RT-PCR
References:	48

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:	20

Hypothalamus

Expression level:	Medium
Species:	Human
Technique:	RT-PCR
References:	20

Heart, liver, foetal liver, kidney, muscle, macrophages, pancreas, prostate, placenta, cartilage, bone

Expression level:	Low
Species:	Human
Technique:	RT-PCR
References:	20

Large dorsal root ganglion neurons

Species:	Human
Technique:	Immunohistochemistry
References:	40

Caudate nucleus, nucleus accumbens, putamen, striatum

Expression level:	High
Species:	Human
Technique:	RT-PCR
References:	20

Cell lines: NT-2 PRE, lymphocytes

Expression level:	High
Species:	Human
Technique:	RT-PCR
References:	20

Osteoclasts and osteoblasts

Species:	Human
Technique:	Immunohistochemistry, qPCR
References:	69

Ovarian cancer cell lines (OVCAR3, A2780), prostate cancer cell lines (PC-3, DU145, LNCaP)

Species:	Human
Technique:	Western blot, immunohistochemistry, qPCR
References:	57

Brain, lung, colon

Expression level:	Medium
Species:	Human
Technique:	RT-PCR
References:	48

MDA-MB-231 breast cancer cell line

Species:	Human
Technique:	qRT-PCR
References:	17

Cancer cell lines

Species:	Human
Technique:	Immunocytochemistry
References:	3,25

Schwann cells

Species:	Mouse
Technique:	Immunohistochemistry
References:	15

Adrenal, GI tract, CNS, brain

Species:	Mouse
Technique:	qPCR
References:	60

Osteoclasts and osteoblasts

Species:	Mouse
Technique:	Immunohistochemistry, qPCR
References:	69

Microglia

Species:	Mouse
Technique:	qPCR
References:	56

Spleen, intestine, fetal tissues, hippocampus, thalamic nuclei, midbrain

Species:	Rat
Technique:	Northern blot; in situ hybridization
References:	61

Cerebellar granule cells

Species:	Rat
Technique:	RT-PCR
References:	14

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:	16

Islets of Langerhans (pancreatic β-cells)

Species:	Rat
Technique:	RT-qPCR, Western blot, double immunofluorescence
References:	58

Submucosa and mesenteric plexus of gut

Species:	Rat
Technique:	Immunohistochemistry
References:	41

Tissue Distribution Comments

GPR55 is expressed in adipose tissue and certain vascular beds [6]. LPS and IFN-γ reduce GPR55 mRNA expression in primary microglial cells [56]. Although GPR55 has been detected in the gut, it is not clear whether these receptors mediate the pharmacological effects of acylethanolamides [8]. GPR55 is present in brain tissue, with the necessary component for LPI signalling via this receptor [70]. GPR55 is expressed in human blood neutrophils [7]. 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 [47].

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) [27]. Receptor expression in adipocytes of subcutaneous and visceral tissue is positively correlated with weight and BMI [45]. 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 [63].

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

GPR55 inhibits M-type K⁺ current

Species:	Human
Tissue:	HEK-293 transfected cells
Response measured:	Patch clamp
References:	40

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:	69

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:	57

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:	48

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:	17

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:	27

LPI increases intracellular Ca²⁺ concentration, RhoA activity and ERK_1/2 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:	47

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:	9

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:	35

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:	19

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:	58

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 [7].

The antiproliferative effects of GPR55 activation in cholangiocarcinoma require JNK activity and lipid rafts [27].

Physiological Functions

GPR55 mediates cell death in maternal uterine tissues

Species:	Rat
Tissue:	Decidual cells
References:	16

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:	13

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:	62

Physiological Functions Comments

GPR55 may be involved in mediating antinociceptive effects, suggested by assays involving weak cannabinoid receptor agonists PEA and AM251 [46].

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:	4,28,69

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:	24,72

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:	23,31

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:	67

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:	17,25

Stimulatory effects on osteoclast function were attenuated in osteoclasts generated from GPR55^-/- macrophages

Species:	Mouse
Tissue:	Osteoclasts
Technique:	Gene knockouts
References:	69

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:	27

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:	47

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 [45].

Phenotypes, Alleles and Disease Models

Mouse data from MGI

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Allele	Composition & genetic background	Accession	Phenotype Id	Phenotype	Reference
Gpr55^tm1.1Mijr	Gpr55^tm1.1Mijr/Gpr55^tm1.1Mijr involves: 129S1/Sv * 129X1/SvJ * C57BL/6	MGI:2685064	MP:0000130	abnormal cancellous bone morphology	PMID: 19805329
Gpr55^tm1.1Mijr	Gpr55^tm1.1Mijr/Gpr55^tm1.1Mijr involves: 129S1/Sv * 129X1/SvJ * C57BL/6	MGI:2685064	MP:0008396	abnormal osteoclast differentiation	PMID: 19805329
Gpr55^tm1.1Mijr	Gpr55^tm1.1Mijr/Gpr55^tm1.1Mijr involves: 129S1/Sv * 129X1/SvJ * C57BL/6	MGI:2685064	MP:0004982	abnormal osteoclast morphology	PMID: 19805329
Gpr55^tm1.1Mijr	Gpr55^tm1.1Mijr/Gpr55^tm1.1Mijr involves: 129S1/Sv * 129X1/SvJ * C57BL/6	MGI:2685064	MP:0001541	abnormal osteoclast physiology	PMID: 19805329
Gpr55^tm1.1Mijr	Gpr55^tm1.1Mijr/Gpr55^tm1.1Mijr involves: 129S1/Sv * 129X1/SvJ * C57BL/6	MGI:2685064	MP:0008872	abnormal physiological response to xenobiotic	PMID: 19805329
Gpr55^tm1.1Mijr	Gpr55^tm1.1Mijr/Gpr55^tm1.1Mijr involves: 129S1/Sv * 129X1/SvJ * C57BL/6	MGI:2685064	MP:0004985	decreased osteoclast cell number	PMID: 19805329
Gpr55^tm1.1Mijr	Gpr55^tm1.1Mijr/Gpr55^tm1.1Mijr involves: 129S1/Sv * 129X1/SvJ * C57BL/6	MGI:2685064	MP:0005605	increased bone mass	PMID: 19805329
Gpr55^tm1.1Mijr	Gpr55^tm1.1Mijr/Gpr55^tm1.1Mijr involves: 129S1/Sv * 129X1/SvJ * C57BL/6	MGI:2685064	MP:0004984	increased osteoclast cell number	PMID: 19805329
Gpr55^tm1Lex	Gpr55^tm1Lex/Gpr55^tm1Lex 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 [29].

Gene Expression and Pathophysiology Comments

A role for GPR55 in mechanical hypersensitivity makes the receptor a novel target for analgesic therapy [39,65]. GPR55 has been shown to mediate anchorage dependent and independent cell proliferation in prostate cancer and ovarian cancer cell lines in vitro [57]. 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 [41].

Biologically Significant Variants

Type:	Single nucleotide polymorphism
Species:	Human
Amino acid change:	V103I
Global MAF (%):	2
Subpopulation MAF (%):	AFR\|AMR: 10\|1
Minor allele count:	T=0.024/53
SNP accession:	rs80290067
Validation:	1000 Genomes, Frequency

Type:	Single nucleotide polymorphism
Species:	Human
Amino acid change:	G195V
Global MAF (%):	17
Subpopulation MAF (%):	AFR\|AMR\|ASN\|EUR: 38\|8\|15\|8
Minor allele count:	A=0.166/363
SNP accession:	VAR_024257, rs3749073
Validation:	1000 Genomes, HapMap, Frequency

Type:	Single nucleotide polymorphism
Species:	Human
Amino acid 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:	VAR_049395, rs34229723
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 [60]. However, more recently Oka et al. [49] has refuted these claims and presented evidence that GPR55 is an intrinsic receptor for lysophosphatidylinositol (LPI). Further reports [19] and [50] 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 [55]. 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 [38]. Phylogenetic analysis of the endocannabinoid system suggests that functional GPR55 receptors are limited to mammals [43]. The endocannabinoid system is collectively under strong purifying selection, although some genes show evidence of adaptive evolution [44]. Zebrafish express no ortholog for GPR55 [42].

The established and unknown pharmacology of GPR55 is summarised in the review by Ross (2009) [59].

References

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66. Sumida H, Lu E, Chen H, Yang Q, Mackie K, Cyster JG. (2017) GPR55 regulates intraepithelial lymphocyte migration dynamics and susceptibility to intestinal damage. Sci Immunol, 2 (18). [PMID:29222090]

67. Vezzulli L, Guzmán CA, Colwell RR, Pruzzo C. (2008) Dual role colonization factors connecting Vibrio cholerae's lifestyles in human and aquatic environments open new perspectives for combating infectious diseases. Curr Opin Biotechnol, 19 (3): 254-9. [PMID:18501582]

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70. Yamashita A, Kumazawa T, Koga H, Suzuki N, Oka S, Sugiura T. (2010) Generation of lysophosphatidylinositol by DDHD domain containing 1 (DDHD1): Possible involvement of phospholipase D/phosphatidic acid in the activation of DDHD1. Biochim Biophys Acta, 1801 (7): 711-20. [PMID:20359546]

71. Yin H, Chu A, Li W, Wang B, Shelton F, Otero F, Nguyen DG, Caldwell JS, Chen YA. (2009) Lipid G protein-coupled receptor ligand identification using beta-arrestin PathHunter assay. J Biol Chem, 284: 12328-12338. [PMID:19286662]

72. Zhang X, Maor Y, Wang JF, Kunos G, Groopman JE. (2010) Endocannabinoid-like N-arachidonoyl serine is a novel pro-angiogenic mediator. Br J Pharmacol, 160 (7): 1583-94. [PMID:20649563]

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