Disease relevance of CNR2

• We recently showed that activation of hepatic cannabinoid CB2 receptors limits progression of experimental liver fibrosis [1].
• The migration induced by 2-arachidonoylglycerol was blocked by treatment of the cells with either SR144528, a CB2 receptor antagonist, or pertussis toxin, suggesting that the CB2 receptor and Gi/Go are involved in the 2-arachidonoylglycerol-induced migration [2].
• In contrast with their role in THC-mediated death, both CB1 and CB2 partially protected glioma against AEA-induced apoptosis [3].
• The cannabinergic proteins currently being explored, which include the CB1 and CB2 receptors, FAAH and the anandamide transporter, are excellent targets for the development of therapeutically useful drugs for a range of conditions including pain, loss of appetite, immunosuppression, peripheral vascular disease and motor disorders [4].
• Cannabinoids inhibit human keratinocyte proliferation through a non-CB1/CB2 mechanism and have a potential therapeutic value in the treatment of psoriasis [5].

Psychiatry related information on CNR2

• These studies suggest that marijuana smoking and immune activation can alter the basal levels of CB1 and CB2 in PBMCs [6].
• Cannabinoid CB2 receptors and fatty acid amide hydrolase are selectively overexpressed in neuritic plaque-associated glia in Alzheimer's disease brains [7].
• The endocannabinoid system, consisting of two cannabinoid receptors (CB1 and CB2) and the endogenous ligands anandamide (arachidonoylethanolamide (AEA)) and 2-arachidonoylglycerol (2-AG), has been shown to control food intake in both animals and humans, modulating either rewarding or quantitative aspects of the eating behavior [8].
• This multifocal expression of CB2 immunoreactivity in brain suggests that CB2 receptors may play broader roles in the brain than previously anticipated and may be exploited as new targets in the treatment of depression and substance abuse [9].

High impact information on CNR2

• Research of cannabinoid actions was boosted in the 1990s by remarkable discoveries including identification of endogenous compounds with cannabimimetic activity (endocannabinoids) and the cloning of their molecular targets, the CB1 and CB2 receptors [10].
• Little is known about signal transduction mechanisms utilized by CB2 receptors [11].
• CB2 immunoreactivity was seen in the epithelium of colonic tissue characteristic of inflammatory bowel disease [12].
• CB1- and CB2-receptor expression was present on plasma cells in the lamina propria, whereas only CB2 was present on macrophages [12].
• Increased epithelial CB2-receptor expression in human inflammatory bowel disease tissue implies an immunomodulatory role that may impact on mucosal immunity [12].

Chemical compound and disease context of CNR2

• Actin polymerization induced by 2-AG was abolished when cells were treated with SR144528, a CB2 receptor antagonist, and pertussis toxin, suggesting that the response was mediated by the CB2 receptor and G(i/o) [13].
• Activation of the CB2 receptor by various tricyclic cannabinoids inhibits adenylate cyclase activity and this inhibition is pertussis toxin sensitive indicating that this receptor is coupled to the Gi/G(o) GTP-binding proteins [14].
• 3 The selective CB2 receptor ligands JWH-015 and indomethacin morpholinylamide (BML-190), when added to THP-1 cells before stimulation with lipopolysaccharide (LPS) and IFN-gamma, reduced the toxicity of their culture supernatants to SH-SY5Y cells [15].
• The effects of CB1 and CB2 receptor agonists and antagonists on the abdominal contractile response to colorectal distension (CRD) in basal conditions and after 2,4,6-trinitrobenzenesulphonic acid-induced colitis were investigated [16].
• The specificity of CB2 is critically dependent on the presence of a lysine (Lys) residue in position 253, not only for binding but also for killing the spirochete [17].

Biological context of CNR2

• We found a significant association of single polymorphisms (P = 0.0014) and haplotypes (P = 0.0001) encompassing the CNR2 gene on human chromosome 1p36, whereas we found no convincing association for CNR1 [18].
• The CB2 receptor is found predominantly in the spleen and in haemopoietic cells and has only 44% overall nucleotide sequence identity with the CB1 receptor [19].
• In this study, we examined the distribution of the cannabinoid receptors, CB1 and CB2, and the endocannabinoid-metabolizing enzyme FAAH in first trimester human placenta [20].
• In addition, the hit molecules from the virtual screening of CB2 receptor ligands (reported previously in Salo et al. J. Med. Chem. 2005, 48, 7166) were also tested in our FAAH assay, and four active compounds (7-10) were found with IC50 values between 0.52 and 22 microM [21].
• Collectively, these results demonstrate reduced endogenous fatty acid amide immunomodulatory responses in individuals with the CB2 188-189 GG/GG genotype and suggest that this CB2 gene variation may be a risk factor for autoimmunity [22].

Anatomical context of CNR2

• Dual immunohistochemical analysis revealed that B lymphocytes express the CB2 protein abundantly [23].
• Upon stimulation with either of the CB2 ligands JWH015 and 2-arachidonoylglycerol (2-AG), neutrophil-like HL60 cells rapidly extended and retracted one or more pseudopods containing F-actin in different directions instead of developing front/rear polarity typically exhibited by migrating leukocytes [24].
• Using [(35)S]Sch225336, we assayed hemopoietic cells and cell lines to quantitate the expression and pharmacology of hCB2 [25].
• 2-arachidonoylglycerol induces the migration of HL-60 cells differentiated into macrophage-like cells and human peripheral blood monocytes through the cannabinoid CB2 receptor-dependent mechanism [2].
• On the other hand, the physiological roles of the CB2 receptor, which is abundantly expressed in several types of leukocytes such as macrophages, still remain unknown [2].

Associations of CNR2 with chemical compounds

• The CB2 receptor mediates inhibition of adenylate cyclase and activation of mitogen-activated protein kinase [19].
• Moreover, treatment of cells with RhoA-dependent protein kinase (p160-ROCK) inhibitor Y27632 yielded cytoskeletal organization similar to that of CB2-stimulated cells [24].
• These studies compare and contrast the potency and efficacy of anandamide, 2-AG, and the synthetic cannabinoid HU210 at hCB2 [26].
• The serine residue, unique to the CB2 receptor, was then mutated to glycine in the K109A mutant [27].
• Role of a conserved lysine residue in the peripheral cannabinoid receptor (CB2): evidence for subtype specificity [27].

Physical interactions of CNR2

• The observation that the phenolic hydroxyl of THCs was important for binding to the CB1 receptor but not as critical for binding to the CB2 receptor prompted us to extend this finding to the cannabinol (CBN) series [28].
• These results demonstrate that the CB2 receptor is functionally coupled to inhibition of adenylyl cyclase activity via a pertussis toxin-sensitive G protein [29].

Regulatory relationships of CNR2

• In contrast to B cells in the MZ or MGZ, CB2-expressing cells in the GCs coexpress the costimulatory membrane protein CD40, which is mainly expressed in the GCs and at very low levels in the MZs and MGZs and the proliferation marker Ki-67 [23].
• The results also support the proposition that the CB2 receptor may represent a novel pharmacological target for selective agonists designed to suppress autoreactive immune responses while avoiding CB1 receptor-mediated cannabinoid adverse effects [22].
• In addition, this CB2 agonist markedly inhibited IFN-gamma-induced phosphorylation of JAK/STAT1 [30].
• Furthermore, our data suggest that TGF-beta actively regulates lymphocyte CB2 receptor expression in an autocrine and paracrine manner [31].

Other interactions of CNR2

• The candidate genes LAMC1, NPR1, and CNR2 were excluded from the region by linkage [32].
• Using the human Raji B cell line as a model, we demonstrate in a transwell assay that moderate migration occurs upon stimulation of the CB2 receptor with the endocannabinoid 2-arachidonoylglycerol, which is enhanced by CD40 costimulation [23].
• First "hybrid" ligands of vanilloid TRPV1 and cannabinoid CB2 receptors and non-polyunsaturated fatty acid-derived CB2-selective ligands [33].
• These findings support a role for p38 MAPK in CB2 receptor-induced apoptosis of human leukaemia cells [34].
• 2-Arachidonoylglycerol (2-AG), an endogenous cannabionoid receptor (CB1 and CB2) ligand, enhanced the adhesion of HL-60 cells differentiated into macrophage-like cells to fibronectin and the vascular cell adhesion molecule-1 [35].

Analytical, diagnostic and therapeutic context of CNR2

• Cell surface expression of CB2 on HL60 cells, on neutrophil-like HL60 cells, and on human neutrophils was confirmed by flow cytometry [24].
• Site-directed mutagenesis was employed as a means of mapping the ligand recognition site for the human CB2 cannabinoid receptor [27].
• The expression of TRPV1, CB1 and CB2 receptor mRNA and proteins were demonstrated by RT-PCR and polyclonal antibodies, respectively [36].
• The prevailing expression of the CB2 gene in immune tissues was confirmed by Northern-blot analysis [37].
• These discoveries have led to the development of CB1- and CB2-selective agonists and antagonists and of bioassays for characterizing such ligands [38].

References