https://onlinelibrary.wiley.com/doi/abs/10.1111/add.14540]]>
Tag Archives: G-Protein coupled receptors
Δ9-Tetrahydrocannabinol and Cannabidiol Differentially Regulate Intraocular Pressure.
“It has been known for nearly 50 years that cannabis and the psychoactive constituent Δ9-tetrahydrocannabinol (THC) reduce intraocular pressure (IOP).
Elevated IOP remains the chief hallmark and therapeutic target for glaucoma, a major cause of blindness.
THC likely acts via one of the known cannabinoid-related receptors (CB1, CB2, GPR18, GPR119, GPR55) but this has never been determined explicitly.
Cannabidiol (CBD) is a second major constituent of cannabis that has been found to be without effect on IOP in most studies.
RESULTS:
We now report that a single topical application of THC lowered IOP substantially (∼28%) for 8 hours in male mice. This effect is due to combined activation of CB1 and GPR18 receptors each of which has been shown to lower ocular pressure when activated. We also found that the effect was sex-dependent, being stronger in male mice, and that mRNA levels of CB1 and GPR18 were higher in males. Far from inactive, CBD was found to have two opposing effects on ocular pressure, one of which involved antagonism of tonic signaling. CBD prevents THC from lowering ocular pressure.CONCLUSIONS:
We conclude that THC lowers IOP by activating two receptors-CB1 and GPR18-but in a sex-dependent manner. CBD, contrary to expectation, has two opposing effects on IOP and can interfere with the effects of THC.” https://www.ncbi.nlm.nih.gov/pubmed/30550613 https://iovs.arvojournals.org/article.aspx?articleid=2718702Novel inverse agonists for the orphan G protein-coupled receptor 6.
“The orphan G protein-coupled receptor 6 (GPR6) displays unique promise as a therapeutic target for the treatment of neuropsychiatric disorders due to its high expression in the striatopallidal neurons of the basal ganglia. GPR6, along with closely related orphan receptors GPR3 and GPR12, are phylogenetically related to CB1 and CB2 cannabinoid receptors. In the current study, we performed concentration-response studies on the effects of three different classes of cannabinoids: endogenous, phyto-, and synthetic, on both GPR6-mediated cAMP accumulation and β-arrestin2 recruitment. In addition, structure-activity relationship studies were conducted on cannabidiol (CBD), a recently discovered inverse agonist for GPR6. We have identified four additional cannabinoids, cannabidavarin (CBDV), WIN55212-2, SR141716A and SR144528, that exert inverse agonism on GPR6. Furthermore, we have discovered that these cannabinoids exhibit functional selectivity toward the β-arrestin2 recruitment pathway. These novel, functionally selective inverse agonists for GPR6 can be used as research tools and potentially developed into therapeutic agents.” https://www.ncbi.nlm.nih.gov/pubmed/30480157]]>
Anti-neuroinflammatory effects of GPR55 antagonists in LPS-activated primary microglial cells.
“Neuroinflammation plays a vital role in Alzheimer’s disease and other neurodegenerative conditions. The orphan G-protein-coupled receptor 55 (GPR55) has been reported to modulate inflammation and is expressed in immune cells such as monocytes and microglia.
Targeting GPR55 might be a new therapeutic option to treat neurodegenerative diseases with a neuroinflammatory background such as Alzheimer’s disease, Parkinson, and multiple sclerosis (MS).”
https://www.ncbi.nlm.nih.gov/pubmed/30453998 https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-018-1362-7 “Pharmacological characterization of GPR55, a putative cannabinoid receptor.” https://www.ncbi.nlm.nih.gov/pubmed/20298715 “Our findings also suggest that GPR55 may be a new pharmacological target for the following C. sativa constituents: Δ9-THCV, CBDV, CBGA, and CBGV. These Cannabis sativa constituents may represent novel therapeutics targeting GPR55.” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3249141/]]>Activation of GPR55 induces neuroprotection of hippocampal neurogenesis and immune responses of neural stem cells following chronic, systemic inflammation.
“New neurons are continuously produced by neural stem cells (NSCs) within the adult hippocampus. Numerous diseases, including major depressive disorder and HIV-1 associated neurocognitive disorder, are associated with decreased rates of adult neurogenesis. A hallmark of these conditions is a chronic release of neuroinflammatory mediators by activated resident glia.
Recent studies have shown a neuroprotective role on NSCs of cannabinoid receptor activation. Yet, little is known about the effects of GPR55, a candidate cannabinoid receptor, activation on reductions of neurogenesis in response to inflammatory insult.
In the present study, we examined NSCs exposed to IL-1β in vitro to assess inflammation-caused effects on NSC differentiation and the ability of GPR55 agonists to attenuate NSC injury.
Taken together, these results suggest a neuroprotective role of GPR55 activation on NSCs in vitro and in vivo and that GPR55 provides a novel therapeutic target against negative regulation of hippocampal neurogenesis by inflammatory insult.”
“The 
“Osteosarcoma is the most common primary malignant tumor of bone in children and adolescents.
Bortezomib (BTZ) is an approved anticancer drug, classified as a selective reversible inhibitor of the ubiquitin-dependent proteasome system, that leads to cancer cell cycle arrest and apoptosis reducing the invasion ability of Osteosarcoma cells in vitro. It also regulates the RANK/RANKL/OPG system, involved in the pathogenesis of bone tumors and in cell migration.
A side effect of BTZ is to induce painful sensory peripheral neuropathy which lead to cessation of therapy or dose reduction.
Recently BTZ has been evaluated in combination with 
“Triple negative breast cancer (TNBC) is the deadliest form of breast cancer because compared with other types of breast cancer, it is more aggressive, diagnosed at later stage and more likely to develop recurrence.
Many patients do not experience adequate tumor control after current clinical treatments involving surgical removal, chemotherapy and/or radiotherapy, leading to disease progression and significantly decreased quality of life.
Here we report a new combinatory therapy strategy involving