Tag Archives: G-Protein coupled receptors

The Important Role of the Endocannabinoid System and the Endocannabinoidome in Gut Health.

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Image result for Altern Ther Health Med journal “The endocannabinoid system is an endogenous pathway comprised of the cannabinoid receptors 1 and 2 (CB1 and CB2), their endogenous ligands known as endocannabinoids, and the enzymes responsible for their synthesis and degradation. The endocannabinoidome extends this system to include other receptors such as TRPV1, PPARα, GPR55 and 5-HT1A. An extensive amount of research is now linking the endocannabinoidome to intestinal health through fascinating mechanisms that include endocannabinoid receptor expression in the gut and interplay with the intestinal microbiota. A dysregulated endocannabinoid system may lead to inflammatory bowel disease and colon cancer.”

https://www.ncbi.nlm.nih.gov/pubmed/31202201

Selective modulation of the cannabinoid type 1 (CB1) receptor as an emerging platform for the treatment of neuropathic pain.

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“Neuropathic pain is caused by a lesion or dysfunction in the nervous system, and it may arise from illness, be drug-induced or caused by toxin exposure. Since the discovery of two G-protein-coupled cannabinoid receptors (CB1 and CB2) nearly three decades ago, there has been a rapid expansion in our understanding of cannabinoid pharmacology. This is currently one of the most active fields of neuropharmacology, and interest has emerged in developing cannabinoids and other small molecule modulators of CB1 and CB2 as therapeutics for neuropathic pain. This short review article provides an overview of the chemotypes currently under investigation for the development of novel neuropathic pain treatments targeting CB1 receptors.”

 https://www.ncbi.nlm.nih.gov/pubmed/31191856
https://pubs.rsc.org/en/content/articlelanding/2019/MD/C8MD00595H#!divAbstract
Graphical abstract: Selective modulation of the cannabinoid type 1 (CB1) receptor as an emerging platform for the treatment of neuropathic pain

Novel CB1-ligands maintain homeostasis of the endocannabinoid-system in ω3- and ω6-long chain-PUFA deficiency.

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The Journal of Lipid Research“Mammalian ω3- and ω6-PUFAs are synthesized from essential fatty acids (EFAs) or supplied by the diet. PUFAs are constitutive elements of membrane-architecture and precursors of lipid signaling molecules. EFAs and long chain PUFAs are precursors in the synthesis of endocannabinoid-ligands of the Gi/o-protein coupled cannabinoid receptors 1 and 2 in the endocannabinoid-system, which critically regulates energy homeostasis, as metabolic signaling system in hypothalamic neuronal circuits, and behavioral parameters. We utilized the auxotrophic fatty acid desaturase 2 deficient (fads2-/-) mouse, deficient in long chain PUFA-synthesis, to follow the age dependent dynamics of the PUFA pattern in the CNS-phospholipidome in unbiased dietary studies of three cohorts on sustained long chain PUFA-free, ω6-arachidonic and ω3-docosahexaenoic acid supplemented diets and their impact on the precursor pool of CB1 ligands. We discovered the transformation of eicosa-all cis-5,11,14-trienoic acid, uncommon in mammalian lipidomes, into two novel endocannabinoids, 20:35,11,14-ethanolamide and 2-20:35,11,14-glycerol, acting as ligands of CB1 in HEK293-cells. Labeling experiments excluded a Δ8-desaturase activity and proved the position-specificity of FADS2. The fads2 -/- mutant might serve as an unbiased model in vivo in the development of novel CB1-agonists and antagonists.”

https://www.ncbi.nlm.nih.gov/pubmed/31167809

http://www.jlr.org/content/early/2019/06/05/jlr.M094664

l-α-Lysophosphatidylinositol (LPI) aggravates myocardial ischemia/reperfusion injury via a GPR55/ROCK-dependent pathway.

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Pharmacology Research & Perspectives banner

“The phospholipid l-α-lysophosphatidylinositol (LPI), an endogenous ligand for GPR55, is elevated in patients with acute coronary syndrome, and a GPR55 antagonist cannabidiol (CBD) reduces experimental ischemia/reperfusion (I/R) injury.”

https://www.ncbi.nlm.nih.gov/pubmed/31149342

https://bpspubs.onlinelibrary.wiley.com/doi/full/10.1002/prp2.487

Cannabinoid receptors as therapeutic targets for autoimmune diseases: where do we stand?

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Drug Discovery Today

“Described during the late 1980s and 1990s, cannabinoid receptors (CB1R and CB2R) are G-protein-coupled receptors (GPCRs) activated by endogenous ligands and cannabinoid drug compounds, such as Δ9-THC. Whereas CB1R has a role in the regulation of neurotransmission in different brain regions and mainly mediates the psychoactive effects of cannabinoids, CB2R is found predominantly in the cells and tissues of the immune system and mediates anti-inflammatory and immunomodulatory processes. Studies have demonstrated that CB1R and CB2R can affect the activation of T cells, B cells, monocytes, and microglial cells, inhibiting proinflammatory cytokine expression and upregulating proresolution mediators. Thus, in this review, we summarize the mechanisms by which CBRs interact with the autoimmune environment and the potential to suppress the development and activation of autoreactive cells. Finally, we highlight how the modulation of CB1R and CB2R is advantageous in the treatment of autoimmune diseases, including multiple sclerosis (MS), type 1 diabetes mellitus (T1DM) and rheumatoid arthritis (RA).”

https://www.ncbi.nlm.nih.gov/pubmed/31158514

https://www.sciencedirect.com/science/article/pii/S1359644618304847?via%3Dihub

Modulation of the Endocannabinoid System as a Potential Anticancer Strategy.

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 Image result for frontiers in pharmacology“Currently, the involvement of the endocannabinoid system in cancer development and possible options for a cancer-regressive effect of cannabinoids are controversially discussed. In recent decades, a number of preclinical studies have shown that cannabinoids have an anticarcinogenic potential. Therefore, especially against the background of several legal simplifications with regard to the clinical application of cannabinoid-based drugs, an extended basic knowledge about the complex network of the individual components of the endocannabinoid system is required. The canonical endocannabinoid system consists of the endocannabinoids N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol as well as the Gi/o protein-coupled transmembrane cannabinoidreceptors CB1 and CB2. As a result of extensive studies on the broader effect of these factors, other fatty acid derivatives, transmembrane and intracellular receptors, enzymes and lipid transporters have been identified that contribute to the effect of endocannabinoids when defined in the broad sense as “extended endocannabinoid system.” Among these additional components, the endocannabinoid-degrading enzymes fatty acid amide hydrolase and monoacylglycerol lipase, lipid transport proteins of the fatty acid-binding protein family, additional cannabinoid-activated G protein-coupled receptors such as GPR55, members of the transient receptor family, and peroxisome proliferator-activated receptors were identified as targets for possible strategies to combat cancer progression. Other endocannabinoid-related fatty acids such as 2-arachidonoyl glyceryl ether, O-arachidonoylethanolamine, N-arachidonoyldopamine and oleic acid amide showed an effect via cannabinoid receptors, while other compounds such as endocannabinoid-like substances exert a permissive action on endocannabinoid effects and act via alternative intracellular target structures. This review gives an overview of the modulation of the extended endocannabinoid system using the example of anticancer cannabinoid effects, which have been described in detail in preclinical studies.”

https://www.ncbi.nlm.nih.gov/pubmed/31143113

“In addition to the palliative effects of cannabinoid compounds in cancer treatment, the endocannabinoid system provides several targets for systemic anticancer treatment. Accordingly, preclinical studies suggest cannabinoids inhibit cancer progression via inhibition of cancer cell proliferation, neovascularization, invasion and chemoresistance, as well as induction of apoptosis, autophagy and increase of tumor immune surveillance.”

https://www.frontiersin.org/articles/10.3389/fphar.2019.00430/full

Towards A Molecular Understanding of The Cannabinoid Related Orphan Receptor GPR18: A Focus on Its Constitutive Activity.

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“The orphan G-protein coupled receptor (GPCR), GPR18, has been recently proposed as a potential member of the cannabinoid family as it recognizes several endogenous, phytogenic, and synthetic cannabinoids. Potential therapeutic applications for GPR18 include intraocular pressure, metabolic disorders, and cancer. GPR18 has been reported to have high constitutive activity, i.e., activation/signaling occurs in the absence of an agonist. This activity can be reduced significantly by the A3.39N mutation. At the intracellular (IC) ends of (transmembrane helices) TMH3 and TMH6 in GPCRs, typically, a pair of oppositely charged amino acids form a salt bridge called the “ionic lock”. Breaking of this salt bridge creates an IC opening for coupling with G protein. The GPR18 “ionic lock” residues (R3.50/S6.33) can form only a hydrogen bond. In this paper, we test the hypothesis that the high constitutive activity of GPR18 is due to the weakness of its “ionic lock” and that the A3.39N mutation strengthens this lock. To this end, we report molecular dynamics simulations of wild-type (WT) GPR18 and the A3.39N mutant in fully hydrated (POPC) phophatidylcholine lipid bilayers. Results suggest that in the A3.39N mutant, TMH6 rotates and brings R3.50 and S6.33 closer together, thus strengthening the GPR18 “ionic lock”.”

https://www.ncbi.nlm.nih.gov/pubmed/31075933

https://www.mdpi.com/1422-0067/20/9/2300

The Endocannabinoid System as a Target in Cancer Diseases: Are We There Yet?

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“The endocannabinoid system (ECS) has been placed in the anti-cancer spotlight in the last decade. The immense data load published on its dual role in both tumorigenesis and inhibition of tumor growth and metastatic spread has transformed the cannabinoid receptors CB1 (CB1R) and CB2 (CB2R), and other members of the endocannabinoid-like system, into attractive new targets for the treatment of various cancer subtypes.

Although the clinical use of cannabinoids has been extensively documented in the palliative setting, clinical trials on their application as anti-cancer drugs are still ongoing. As drug repurposing is significantly faster and more economical than de novo introduction of a new drug into the clinic, there is hope that the existing pharmacokinetic and safety data on the ECS ligands will contribute to their successful translation into oncological healthcare.

CB1R and CB2R are members of a large family of membrane proteins called G protein-coupled receptors (GPCR). GPCRs can form homodimers, heterodimers and higher order oligomers with other GPCRs or non-GPCRs. Currently, several CB1R and CB2R-containing heteromers have been reported and, in cancer cells, CB2R form heteromers with the G protein-coupled chemokine receptor CXCR4, the G protein-coupled receptor 55 (GPR55) and the tyrosine kinase receptor (TKR) human V-Erb-B2 Avian Erythroblastic Leukemia Viral Oncogene Homolog 2 (HER2).

These protein complexes possess unique pharmacological and signaling properties, and their modulation might affect the antitumoral activity of the ECS. This review will explore the potential of the endocannabinoid network in the anti-cancer setting as well as the clinical and ethical pitfalls behind it, and will develop on the value of cannabinoid receptor heteromers as potential new targets for anti-cancer therapies and as prognostic biomarkers.”

https://www.ncbi.nlm.nih.gov/pubmed/31024307

https://www.frontiersin.org/articles/10.3389/fphar.2019.00339/full

Future Aspects for Cannabinoids in Breast Cancer Therapy.

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“Cannabinoids (CBs) from Cannabis sativa provide relief for tumor-associated symptoms (including nausea, anorexia, and neuropathic pain) in the palliative treatment of cancer patients.

Additionally, they may decelerate tumor progression in breast cancer patients.

Indeed, the psychoactive delta-9-tetrahydrocannabinol (THC), non-psychoactive cannabidiol (CBD) and other CBs inhibited disease progression in breast cancer models.

The effects of CBs on signaling pathways in cancer cells are conferred via G-protein coupled CB-receptors (CB-Rs), CB1-R and CB2-R, but also via other receptors, and in a receptor-independent way.

THC is a partial agonist for CB1-R and CB2-R; CBD is an inverse agonist for both.

In breast cancer, CB1-R expression is moderate, but CB2-R expression is high, which is related to tumor aggressiveness. CBs block cell cycle progression and cell growth and induce cancer cell apoptosis by inhibiting constitutive active pro-oncogenic signaling pathways, such as the extracellular-signal-regulated kinase pathway.

They reduce angiogenesis and tumor metastasis in animal breast cancer models. CBs are not only active against estrogen receptor-positive, but also against estrogen-resistant breast cancer cells. In human epidermal growth factor receptor 2-positive and triple-negative breast cancer cells, blocking protein kinase B- and cyclooxygenase-2 signaling via CB2-R prevents tumor progression and metastasis.

Furthermore, selective estrogen receptor modulators (SERMs), including tamoxifen, bind to CB-Rs; this process may contribute to the growth inhibitory effect of SERMs in cancer cells lacking the estrogen receptor.

In summary, CBs are already administered to breast cancer patients at advanced stages of the disease, but they might also be effective at earlier stages to decelerate tumor progression.”

 https://www.ncbi.nlm.nih.gov/pubmed/30987191
https://www.mdpi.com/1422-0067/20/7/1673

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

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“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.”

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

https://www.degruyter.com/view/j/jbcpp.2016.27.issue-3/jbcpp-2015-0080/jbcpp-2015-0080.xml