Activation of the orphan receptor GPR55 by lysophosphatidylinositol promotes metastasis in triple-negative breast cancer.

Posted on June 29, 2016 by David

“The orphan G protein-coupled receptor GPR55 has been directly or indirectly related to basic alterations that drive malignant growth: uncontrolled cancer cell proliferation, sustained angiogenesis, and cancer cell adhesion and migration. However, little is known about the involvement of this receptor in metastasis.

Here, we show that elevated GPR55 expression in human tumors is associated with the aggressive basal/triple-negative breast cancer population, higher probability to develop metastases, and therefore poor patient prognosis. Activation of GPR55 by its proposed endogenous ligand lysophosphatidylinositol confers pro-invasive features on breast cancer cells both in vitro and in vivo. Specifically, this effect is elicited by coupling to Gq/11 heterotrimeric proteins and the subsequent activation, through ERK, of the transcription factor ETV4/PEA3.

Together, these data show that GPR55 promotes breast cancer metastasis, and supports the notion that this orphan receptor may constitute a new therapeutic target and potential biomarker in the highly aggressive triple-negative subtype.”

http://www.ncbi.nlm.nih.gov/pubmed/27340777

A Functional Assay for GPR55: Envision Protocol.

Posted on June 2, 2016 by David

“AlphaScreen(®) SureFire(®) assay is a novel technology that combines luminescent oxygen channeling technology, nano-beads, and monocloncal antibodies to detect the level of a selected protein in a volume lower than 5 μl. This method is more sensitive compared with the traditional enzyme-linked immunosorbent assays (ELISA), and can detect an increasing number of new targets. Here, we described a method for AlphaScreen(®) SureFire(®) assay that targets ERK1/2 phosphorylation, a primary downstream signaling pathway that conveys activation of GPR55 by L-α-lysophosphatidylinositol (LPI) and certain cannabinoids.”

http://www.ncbi.nlm.nih.gov/pubmed/27245893

Advances towards the Discovery of GPR55 Ligands.

Posted on April 26, 2016 by David

“The G-protein-coupled receptor 55 (GPR55) was identified in 1999.

It was proposed as a novel member of the endocannabinoid system due to the fact that some endogenous, plant-derived and synthetic cannabinoid ligands act on GPR55. However, the complexity of the cellular downstream signaling pathways related to GPR55 activation delayed the discovery of selective GPR55 ligands.

It was only a few years ago that the high throughput screening of libraries of pharmaceutical companies and governmental organizations allowed to identify selective GPR55 agonists and antagonists. Since then, several GPR55 modulator scaffolds have been reported.

The relevance of GPR55 has been explored in diverse physiological and pathological processes revealing its role in inflammation, neuropathic pain, bone physiology, diabetes and cancer.

Considering GPR55 as a new promising therapeutic target, there is a clear need for new selective and potent GPR55 modulators. This review will address a current structural update of GPR55 ligands.”

http://www.ncbi.nlm.nih.gov/pubmed/27109575

GPR55 – a putative “type 3” cannabinoid receptor in inflammation.

Posted on December 17, 2015 by David

“G protein-coupled receptor 55 (GPR55) shares numerous cannabinoid ligands with CB1 and CB2 receptors despite low homology with those classical cannabinoid receptors. The pharmacology of GPR55 is not yet fully elucidated; however, GPR55 utilizes a different signaling system and downstream cascade associated with the receptor.

Therefore, GPR55 has emerged as a putative “type 3″ cannabinoid receptor, establishing a novel class of cannabinoid receptor.

Furthermore, the recent evidence of GPR55-CB1 and GPR55-CB2 heteromerization along with its broad distribution from central nervous system to peripheries suggests the importance of GPR55 in various cellular processes and pathologies and as a potential therapeutic target in inflammation.”

http://www.ncbi.nlm.nih.gov/pubmed/26669245

The GPR55 antagonist CID16020046 protects against intestinal inflammation.

Posted on August 1, 2015 by David

“G protein-coupled receptor 55 (GPR55) is a lysophospholipid receptor responsive to certain cannabinoids.

The role of GPR55 in inflammatory processes of the gut is largely unknown. Using the recently characterized GPR55 inhibitor CID16020046, we determined the role of GPR55 in experimental intestinal inflammation and explored possible mechanisms of action…

Pharmacological blockade of GPR55 reduces experimental intestinal inflammation by reducing leukocyte migration and activation, in particular that of macrophages. Therefore, CID16020046 represents a possible drug for the treatment of bowel inflammation.”

http://www.ncbi.nlm.nih.gov/pubmed/26227635

Anandamide exerts its antiproliferative actions on cholangiocarcinoma by activation of the GPR55 receptor

Posted on July 13, 2015 by David

“We have previously shown that AEA exerts growth-suppressing effects on cholangiocarcinoma by inducing apoptosis.

At the time, we assumed that AEA was acting via a receptor-independent mechanism.

However, given the recent discovery and characterization of GPR55 as a novel AEA receptor, our data need to be reassessed to determine if GPR55 activation can decrease cholangiocarcinoma cell proliferation.

Thus, our aims are to determine if these AEA-mediated effects on cholangiocarcinoma cell growth can be attributed to the activation of GPR55.

This data represent the first evidence that GPR55 activation by anandamide can lead to the recruitment and activation of the Fas death receptor complex and that targeting GPR55 activation may be a viable option for the development of therapeutic strategies to treat cholangiocarcinoma.

In conclusion, we have clearly demonstrated a role for GPR55 in the antiproliferative effects of AEA in vivo andin vitro…

Cholangiocarcinoma has a very poor prognosis and survival rate; therefore we propose that the development of novel therapeutic strategies that target GPR55 may prove beneficial for the treatment of this devastating disease.

Consistent with our observation that AEA has antiproliferative and pro-apoptotic properties, cannabinoids of various origins (endogenous, plant-derived or synthetic analogues) have been shown to suppress cancer cell growth in vitro as well as in vivo.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3126905/

The Lysophosphatidylinositol Receptor GPR55 Modulates Pain Perception in the Periaqueduactal Grey.

Posted on May 15, 2015 by David

“Emerging evidence indicates the involvement of GPR55 and its proposed endogenous ligand, lysophosphatidylinositol (LPI), in nociception…

Thus, we provide the first pharmacological evidence that GPR55 activation at central levels is pronociceptive, suggesting that interfering with GPR55 signaling in the PAG may promote analgesia.”

http://www.ncbi.nlm.nih.gov/pubmed/25972448

Targeting CB2-GPR55 Receptor Heteromers Modulates Cancer Cell Signaling.

Posted on June 20, 2014 by David

“The G protein-coupled receptors CB2 (CB2R) and GPR55 are overexpressed in cancer cells and human tumors. As a modulation of GPR55 activity by cannabinoids has been suggested, we analyzed whether this receptor participates in cannabinoid effects on cancer cells.

Here, we show that CB2R and GPR55 form heteromers in cancer cells, that these structures possess unique signaling properties, and that modulation of these heteromers can modify the antitumoral activity of cannabinoids in vivo.

These findings unveil the existence of previously unknown signaling platforms that help explain the complex behavior of cannabinoids and may constitute new targets for therapeutic intervention in oncology.”

http://www.ncbi.nlm.nih.gov/pubmed/24942731

http://www.thctotalhealthcare.com/category/cancer/

Role of Endocannabinoid Activation of Peripheral CB1 Receptors in the Regulation of Autoimmune Disease.

Posted on June 10, 2014 by David

“The impact of the endogenous cannabinoids (AEA, 2-AG, PEA, and virodamine) on the immune cell expressed cannabinoid receptors (CB1, CB2, TRPV-1, and GPR55) and consequent regulation of immune function is an exciting area of research with potential implications in the prevention and treatment of inflammatory and autoimmune diseases.

Despite significant advances in understanding the mechanisms through which cannabinoids regulate immune functions, not much is known about the role of endocannabinoids in the pathogenesis or prevention of autoimmune diseases.

Inasmuch as CB2 expression on immune cells and its role has been widely reported, the importance of CB1 in immunological disorders has often been overlooked especially because it is not highly expressed on naive immune cells.

Therefore, the current review aims at delineating the effect of endocannabinoids on CB1 receptors in T cell driven autoimmune diseases. This review will also highlight some autoimmune diseases in which there is evidence indicating a role for endocannabinoids in the regulation of autoimmune pathogenesis.

Overall, based on the evidence presented using the endocannabinoids, specifically AEA, we propose that the peripheral CB1 receptor is involved in the regulation and amelioration of inflammation associated with autoimmune diseases.”

http://www.ncbi.nlm.nih.gov/pubmed/24911431

A potential role for GPR55 in the regulation of energy homeostasis.

Posted on January 1, 2014 by David

“G protein-coupled receptor 55 (GPR55) is a putative cannabinoid receptor that is expressed in several tissues involved in regulating energy homeostasis, including the hypothalamus, gastrointestinal tract, pancreas, liver, white adipose and skeletal muscle.

GPR55 has been shown to have a role in cancer and gastrointestinal inflammation, as well as in obesity and type 2 diabetes mellitus (T2DM).

Despite this, the (patho)physiological role of GPR55 in cell dysfunction is still poorly understood, largely because of the limited identification of downstream signalling targets.

Nonetheless, research has suggested that GPR55 modulation would be a useful pharmacological target in metabolically active tissues to improve treatment of diseases such as obesity and T2DM.

Further research is essential to gain a better understanding of the role that this receptor might have in these and other pathophysiological conditions.”

http://www.ncbi.nlm.nih.gov/pubmed/24370891