GPR55

Official Full Name

G protein-coupled receptor 55

Organism

Homo sapiens

GeneID

9290

Background

This gene belongs to the G-protein-coupled receptor superfamily. The encoded integral membrane protein is a likely cannabinoid receptor. It may be involved in several physiological and pathological processes by activating a variety of signal transduction pathways. [provided by RefSeq, Aug 2013]

Synonyms

LPIR1;

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Detailed Information

Since GPR55 was cloned in 1999 and identified as a novel G-protein coupled receptor (GPCR) highly expressed in the human brain, the mRNA encoding GPR55 has been detected in various regions of the brain and spinal cord including the caudate and putamen, hippocampus, brain stem, hypothalamus, cerebellum, frontal cortex, striatum and dorsal root ganglion (DRG) neurons. So far, it has been established that GPR55 is a potential target for treating osteoporosis, pain, and cancer. A recent study showed a high expression of GPR55 in myenteric colonic neurons and the involvement of the receptor in colonic motility. The role of GPR55 in cancer proliferation has recently been confirmed to be proliferative rather than anti-proliferative. It was not only detected in multiple cancer cell lines such as brain, skin, breast, and prostate but also discovered in many clinical isolates from cancer patients. Moreover, it has been suggested that GPR55 activation stimulates angiogenesis and metastasis, which explains the relationship between GPR55 expression and cancer aggressiveness.

Signalling Pathways for GPR55

Experiments using HEK298 cells overexpressing GPR55 have indicated that GPR55-mediated signalling is facilitated by the coupling of the receptor to Ga13, which results in the activation of small GTPases, including cell division control protein 42 (Cdc42), Ras homologue gene family member A (RhoA), and Ras-related C3 botulinum toxin substrate 1 (Rac1). This leads to the oscillatory release of calcium from the endoplasmic reticulum, which triggers multiple metabolic pathways. Activation of GPR55 also results in phosphorylation and consequent activation of the MAP kinases ERK1/2 by the RhoA-ROCK pathway and/or increases in [^Ca2+]i. The transcription factors NF-κB and CREB, which are downstream of the ERK pathway, are activated by GPR55, as is another transcription factor (ATF-2), although this occurs through p38 MAPK, not via ERK1/2. Besides, GPR55 can also activate the transcription factor NFAT in a RhoA-dependent manner. Once activated, these transcription factors regulate the expression of key genes that are responsible for transducing the effects of GPR55 in a variety of cellular functions including bone resorption, tumorigenesis, and neuropathic pain.

GPR55 Figure 1. Signalling pathways downstream of GPR55 activation. (Liu B, et al., 2015)

Pathophysiological role of GPR55

Several studies have also confirmed a role for GPR55 in the development of nonmetabolic disease. Primarily, this is driven by the study of LPI, an effective endogenous agonist of GPR55. GPR55 expression has been detected in many human cancer cell line models, including cancer models of the pancreas, ovarian, breast, prostate and bile ducts. Recently, GPR55 was identified in a squamous cell carcinoma cell line. There is also a positive correlation between the aggressiveness of cancer and the expression of GPR55. Moreover, overexpression of GPR55 increased cancer cell proliferation by ERK activation, whereas silencing GPR55 had the opposite effect and reduced ERK activation and cancer cell proliferation. Remarkably, GPR55 expression and LPI are associated with cellular proliferation of ovarian, breast, prostate, glioblastoma and migration in breast cancer. Besides, GPR55 has been suggested to be involved in inflammatory and neuropathic pain. GPR55 might have a proinflammatory role in gastrointestinal inflammation, because the severity of colitis in GPR55-knockout mice was significantly lower than that in wild-type mice. Thus, blocking this receptor might be beneficial for the treatment of proinflammatory conditions, such as inflammatory bowel disease (IBD).

References:

Simcocks A C, et al. A potential role for GPR55 in the regulation of energy homeostasis. Drug discovery today, 2014, 19(8): 1145-1151.
Fakhouri L, et al. Design, synthesis and biological evaluation of GPR55 agonists. Bioorganic & medicinal chemistry, 2017, 25(16): 4355-4367.
Liu B, et al. GPR55: from orphan to metabolic regulator? Pharmacology & therapeutics, 2015, 145: 35-42.
Celorrio M, et al. GPR55: A therapeutic target for Parkinson's disease? Neuropharmacology, 2017, 125: 319-332.

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