Tag Archives: G-Protein coupled receptors

Novel protective effect of O-1602 and abnormal cannabidiol, GPR55 agonists, on ER stress-induced apoptosis in pancreatic β-cells.

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Biomedicine & Pharmacotherapy

“Insulin resistance and β-cell dysfunction are the main defects in Type 2 Diabetes Mellitus (T2DM), and β-cell dysfunction and apoptosis is the critical determinant in the progression of T2DM. G-protein coupled receptor 55 (GPR55) is an orphan G-protein coupled receptor, which is activated by endocannabinoids and lipid transmitters. Recently, GPR55 was shown to regulate glucose and energy homeostasis, however its role in β-cell apoptosis was not studied. Therefore, in this study, we investigated the novel effect of GPR55 agonists, O-1602 and abnormal cannabidiol (Abn-CBD), on endoplasmic reticulum (ER) stress-induced apoptosis in mouse pancreatic β-cell lines, MIN6 and Beta-TC-6, and its underlying mechanisms. Our results showed that O-1602 and Abn-CBD reduced ER stress-induced apoptosis in MIN6 and Beta-TC-6 cells. This was through the phosphorylation of 3′-5′-cyclic adenosine monophosphate response element-binding protein (CREB) in β-cells, hence activating CREB downstream anti-apoptotic genes, Bcl-2 and Bcl-xL. Moreover, O-1602 and Abn-CBD directly activated kinases, CaMKIV, Erk1/2 and PKA, to induce CREB phosphorylation. Therefore, our results indicated that GPR55 agonists protected from β-cell apoptosis through CREB activation, thus up-regulating anti-apoptotic genes. In conclusion, our study provided a novel protective effect of GPR55 agonists on ER stress-induced apoptosis in β-cells and its underlying mechanisms mediating this protection, therefore we suggested that GPR55 might be a therapeutic target for T2DM.”

https://www.ncbi.nlm.nih.gov/pubmed/30841431

https://www.sciencedirect.com/science/article/pii/S0753332218375668?via%3Dihub

New Insights of Uterine Leiomyoma Pathogenesis: Endocannabinoid System.

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“The aim of this study was to determine if components of the endocannabinoid system are modulated in uterine leiomyomas (fibroids). Components studied included cannabinoid receptors 1 (CB1) and 2 (CB2); the G protein-coupled receptor GPR55; transient potential vanilloid receptor 1 (TRPV1) and the endocannabinoid modulating enzymes N-acylphosphatidylethanolamine-specific phospholipase D (NAPE-PLD) and fatty acid amide hydrolase (FAAH), and their N-acylethanolamine (NAE) ligands: N-arachidonylethanolamine (AEA), N-oleoylethanolamine (OEA), and N-palmityolethanaolamine (PEA). MATERIAL AND METHODS Transcript levels of CB1, CB2, TRPV1, GPR55, NAPE-PLD, and FAAH were measured using RT-PCR and correlated with the tissue levels of the 3 NAEs in myometrial tissues. The tissues studied were: 1) fibroids, 2) myometrium adjacent/juxtaposed to the fibroid lesions, and 3) normal myometrium. Thirty-seven samples were processed for NAE measurements and 28 samples were used for RT-PCR analyses. RESULTS FAAH expression was significantly lower in fibroids, resulting in a NAPE-PLD: FAAH ratio that favors higher AEA levels in pre-menopausal tissues, whilst PEA levels were significantly lower, particularly in post-menopausal women, suggesting PEA protects against fibroid pathogenesis. The CB1: CB2 ratio was lower in fibroids, suggesting that loss of CB1 expression affects the fibroid cell phenotype. Significant correlations between reduced FAAH, CB1, and GPR55 expression and PEA in fibroids indicate that the loss of these endocannabinoid system components are biomarkers of leiomyomata. CONCLUSIONS Loss of expression of CB1, FAAH, GPR55, and PEA production are linked to the pathogenesis of uterine fibroids and further understanding of this might eventually lead to better disease indicators or the development of therapeutic potentials that might eventually be used in the management of uterine fibroids.”

https://www.ncbi.nlm.nih.gov/pubmed/30842391

https://basic.medscimonit.com/abstract/index/idArt/914019

New Insights in Cannabinoid Receptor Structure and Signaling.

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“Cannabinoid has long been used for medicinal purposes. Cannabinoid signaling has been considered the therapeutic targets for treating pain, addiction, obesity, inflammation, and other diseases. Recent studies have suggested that in addition to CB1 and CB2, there are non-CB1 and non-CB2 cannabinoid-related orphan GPCRs including GPR18, GPR55, and GPR119. In addition, CB1 and CB2 display allosteric binding and biased signaling, revealing correlations between biased signaling and functional outcomes. Interestingly, new investigations have indicated that CB1 is functionally present within mitochondria of striated and heart muscles directly regulating intramitochondrial signaling and respiration.

CONCLUSION:

In this review, we summarize the recent progress in cannabinoid-related orphan GPCRs, CB1/CB2 structure, Gi/Gs coupling, allosteric ligands and biased signaling, and mitochondria-localized CB1, and discuss the future promise of this research.”

https://www.ncbi.nlm.nih.gov/pubmed/30767756

http://www.eurekaselect.com/170011/article

Potential Use of Cannabinoids for the Treatment of Pancreatic Cancer.

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“Cannabinoid extracts may have anticancer properties, which can improve cancer treatment outcomes.

The aim of this review is to determine the potentially utility of cannabinoids in the treatment of pancreatic cancer.

Results: Cannabinol receptors have been identified in pancreatic cancer with several studies showing in vitroantiproliferative and proapoptotic effects. The main active substances found in cannabis plants are cannabidiol (CBD) and tetrahydrocannabinol (THC). There effects are predominately mediated through, but not limited to cannabinoid receptor-1, cannabinoid receptor-2, and G-protein-coupled receptor 55 pathways. In vitro studies consistently demonstrated tumor growth-inhibiting effects with CBD, THC, and synthetic derivatives. Synergistic treatment effects have been shown in two studies with the combination of CBD/synthetic cannabinoid receptor ligands and chemotherapy in xenograft and genetically modified spontaneous pancreatic cancer models. There are, however, no clinical studies to date showing treatment benefits in patients with pancreatic cancer.

Conclusions: Cannabinoids may be an effective adjunct for the treatment of pancreatic cancer. Data on the anticancer effectiveness of various cannabinoid formulations, treatment dosing, precise mode of action, and clinical studies are lacking.”

 https://www.ncbi.nlm.nih.gov/pubmed/30706048
“Endogenous cannabinoids, synthetic or cannabis extracted from plants, can reduce tumor invasion and growth, induce tumor cell death, and inhibit tumor angiogenesis via cannabinoid receptor or receptor-independent pathways. Cannabinoid receptors appear to be highly expressed in pancreatic cancer compared with normal pancreatic tissue. CBD and THC appear to have antiproliferative and proapoptotic effects.”
https://www.liebertpub.com/doi/10.1089/pancan.2018.0019

Cannabinoids and Bone Regeneration.

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 Publication Cover“Bone is a complex tissue of the with unique properties such as high strength and regeneration capabilities while carrying out multiple functions. Bone regeneration occurs both in physiological situations (bone turnover) and pathological situations (e.g. fractures), being performed by osteoblasts and osteoclasts. If this process is inadequate, fracture nonunion or aseptic loosening of implants occurs and requires a complex treatment.

Exogenous factors are currently used to increase bone regeneration process when needed, such as bisphosphonates and vitamin D, but limitations do exist. Cannabinoid system has been shown to have positive effects on bone metabolism. Cannabinoids at bone level mainly act on two receptors called CB-1 and CB-2, but GPR55, GPR119, TPRV1, TPRV4 receptors may also be involved. The CB-2 receptors are found in bone cells at higher levels compared to other receptors.

Endocannabinods represented by anandamide and 2-arachidonoylglycerol, can stimulate osteoblast formation, bone formation and osteoclast activity. CB-2 agonists including HU-308, HU-433, JWH133 and JWH015 can stimulate osteoblast proliferation and activity, while CB-2 antagonists such as AM630 and SR144528 can inhibit osteoclast differentiation and function. CB-1 antagonist AM251 has been shown to inhibit osteoclast differentiation and activity, while GPR55 antagonist cannabidiol increases osteoblast activity and decreases osteoclast function.

An optimal correlation of dose, duration, moment of action and affinity can lead to an increased bone regeneration capacity, with important benefits in many pathological situations which involve bone tissue. As adverse reactions of cannabinoids haven’t been described in patients under controlled medication, cannabinoids can represent future treatment for bone regeneration.”

https://www.ncbi.nlm.nih.gov/pubmed/30702341

https://www.tandfonline.com/doi/abs/10.1080/03602532.2019.1574303?journalCode=idmr20

Targeting CB1 and GPR55 Endocannabinoid Receptors as a Potential Neuroprotective Approach for Parkinson’s Disease.

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 “Cannabinoid CB1 receptors (CB1R) and the GPR55 receptor are expressed in striatum and are potential targets in the therapy of Parkinson’s disease (PD), one of the most prevalent neurodegenerative diseases in developed countries.

The aim of this paper was to address the potential of ligands acting on those receptors to prevent the action of a neurotoxic agent, MPP+, that specifically affects neurons of the substantia nigra due to uptake via the dopamine DAT transporter.

These results show that neurons expressing heteromers are more resistant to cell death but question the real usefulness of CB1R, GPR55, and their heteromers as targets to afford PD-related neuroprotection.”

https://www.ncbi.nlm.nih.gov/pubmed/30687889

https://link.springer.com/article/10.1007%2Fs12035-019-1495-4

Some Prospective Alternatives for Treating Pain: The Endocannabinoid System and Its Putative Receptors GPR18 and GPR55.

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Image result for frontiers in pharmacology“Marijuana extracts (cannabinoids) have been used for several millennia for pain treatment.

Regarding the site of action, cannabinoids are highly promiscuous molecules, but only two cannabinoid receptors (CB1 and CB2) have been deeply studied and classified.

Thus, therapeutic actions, side effects and pharmacological targets for cannabinoids have been explained based on the pharmacology of cannabinoid CB1/CB2 receptors. However, the accumulation of confusing and sometimes contradictory results suggests the existence of other cannabinoid receptors.

Different orphan proteins (e.g., GPR18, GPR55, GPR119, etc.) have been proposed as putative cannabinoid receptors.

According to their expression, GPR18 and GPR55 could be involved in sensory transmission and pain integration.

This work summarized novel data supporting that, besides cannabinoid CB1 and CB2receptors, GPR18 and GPR55 may be useful for pain treatment.

Conclusion: There is evidence to support an antinociceptive role for GPR18 and GPR55.”

https://www.ncbi.nlm.nih.gov/pubmed/30670965

https://www.frontiersin.org/articles/10.3389/fphar.2018.01496/full

Cannabis, cannabinoid receptors, and endocannabinoid system: yesterday, today, and tomorrow

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“Cannabis sativa, is also popularly known as marijuana, has been cultivated and used for recreational and medicinal purposes for many centuries.

The main psychoactive content in cannabis is Δ9-tetrahydrocannabinol (THC). In addition to plant cannabis sativa, there are two classes of cannabinoids—the synthetic cannabinoids (e.g., WIN55212–2) and the endogenous cannabinoids (eCB), anandamide (ANA) and 2-arachidonoylglycerol (2-AG).

The biological effects of cannabinoids are mainly mediated by two members of the G-protein-coupled receptor family, cannabinoid receptors 1 (CB1R) and 2 (CB2R). The endocannabinoids, cannabinoid receptors, and the enzymes/proteins responsible for their biosynthesis, degradation, and re-updating constitute the endocannabinoid system.

In recent decades, the endocannabinoid system has attracted considerable attention as a potential therapeutic target in numerous physiological conditions, such as in energy balance, appetite stimulation, blood pressure, pain modulation, embryogenesis, nausea and vomiting control, memory, learning and immune response, as well as in pathological conditions such as Parkinson’s disease, Huntington’s disease, Alzheimer’s disease, and multiple sclerosis.

The major goal of this Special Issue is to discuss and evaluate the current progress in cannabis and cannabinoid research in order to increase our understanding about cannabinoid action and the underlying biological mechanisms and promote the development cannabinoid-based pharmacotherapies.

 Overall, the present special issue provides an overview and insight on pharmacological mechanisms and therapeutic potentials of cannabis, cannabinoid receptors, and eCB system. I believe that this special issue will promote further efforts to apply cannabinoid ligands as the therapeutic strategies for treating a variety of diseases.”
https://www.ncbi.nlm.nih.gov/pubmed/30670816
https://www.nature.com/articles/s41401-019-0210-3

Structure of a Signaling Cannabinoid Receptor 1-G Protein Complex.

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“Cannabis elicits its mood-enhancing and analgesic effects through the cannabinoid receptor 1 (CB1), a G protein-coupled receptor (GPCR) that signals primarily through the adenylyl cyclase-inhibiting heterotrimeric G protein Gi. Activation of CB1-Gi signaling pathways holds potential for treating a number of neurological disorders and is thus crucial to understand the mechanism of Giactivation by CB1.

Here, we present the structure of the CB1-Gi signaling complex bound to the highly potent agonist MDMB-Fubinaca (FUB), a recently emerged illicit synthetic cannabinoid infused in street drugs that have been associated with numerous overdoses and fatalities.”

https://www.ncbi.nlm.nih.gov/pubmed/30639101

https://linkinghub.elsevier.com/retrieve/pii/S0092867418315654

“Antidepressant-like effect of delta9-tetrahydrocannabinol and other cannabinoids isolated from Cannabis sativa L. Results of this study show that Delta(9)-THC and other cannabinoids exert antidepressant-like actions, and thus may contribute to the overall mood-elevating properties of cannabis.”   https://www.ncbi.nlm.nih.gov/pubmed/20332000

Expression and Preparation of a G-Protein-Coupled Cannabinoid Receptor CB2 for NMR Structural Studies.

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Current Protocols in Protein Science banner

“Cannabinoid receptor type II, or CB2 , is an integral membrane protein that belongs to a large class of G-protein-coupled receptors (GPCR)s. CB2 is a part of the endocannabinoid system, which plays an important role in the regulation of immune response, inflammation, and pain.

Information about the structure and function of CB2 is essential for the development of specific ligands targeting this receptor.

We present here a methodology for recombinant expression of CB2 and its stable isotope labeling, purification, and reconstitution into liposomes, in preparation for its characterization by nuclear magnetic resonance (NMR).

Correctly folded, functional CB2 labeled with [13 C,15 N]tryptophan or uniformly labeled with 13 C and 15 N is expressed in a medium of defined composition, under controlled aeration, pH, and temperature conditions.

The receptor is purified by affinity chromatography and reconstituted into lipid bilayers in the form of proteoliposomes suitable for analysis by NMR spectroscopy.”

https://www.ncbi.nlm.nih.gov/pubmed/30624864

https://currentprotocols.onlinelibrary.wiley.com/doi/abs/10.1002/cpps.83