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Gene Review

CNR2  -  cannabinoid receptor 2 (macrophage)

Homo sapiens

Synonyms: CB-2, CB2, CB2A, CB2B, CX5, ...
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Disease relevance of CNR2


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


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


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


Analytical, diagnostic and therapeutic context of CNR2


  1. CB1 cannabinoid receptor antagonism: a new strategy for the treatment of liver fibrosis. Teixeira-Clerc, F., Julien, B., Grenard, P., Tran Van Nhieu, J., Deveaux, V., Li, L., Serriere-Lanneau, V., Ledent, C., Mallat, A., Lotersztajn, S. Nat. Med. (2006) [Pubmed]
  2. 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. Kishimoto, S., Gokoh, M., Oka, S., Muramatsu, M., Kajiwara, T., Waku, K., Sugiura, T. J. Biol. Chem. (2003) [Pubmed]
  3. Arachidonylethanolamide induces apoptosis of human glioma cells through vanilloid receptor-1. Contassot, E., Wilmotte, R., Tenan, M., Belkouch, M.C., Schnüriger, V., de Tribolet, N., Burkhardt, K., Dietrich, P.Y., Bourkhardt, K. J. Neuropathol. Exp. Neurol. (2004) [Pubmed]
  4. Cannabinergic ligands. Palmer, S.L., Thakur, G.A., Makriyannis, A. Chem. Phys. Lipids (2002) [Pubmed]
  5. Cannabinoids inhibit human keratinocyte proliferation through a non-CB1/CB2 mechanism and have a potential therapeutic value in the treatment of psoriasis. Wilkinson, J.D., Williamson, E.M. J. Dermatol. Sci. (2007) [Pubmed]
  6. Altered cannabinoid receptor mRNA expression in peripheral blood mononuclear cells from marijuana smokers. Nong, L., Newton, C., Cheng, Q., Friedman, H., Roth, M.D., Klein, T.W. J. Neuroimmunol. (2002) [Pubmed]
  7. Cannabinoid CB2 receptors and fatty acid amide hydrolase are selectively overexpressed in neuritic plaque-associated glia in Alzheimer's disease brains. Benito, C., Núñez, E., Tolón, R.M., Carrier, E.J., Rábano, A., Hillard, C.J., Romero, J. J. Neurosci. (2003) [Pubmed]
  8. Blood levels of the endocannabinoid anandamide are increased in anorexia nervosa and in binge-eating disorder, but not in bulimia nervosa. Monteleone, P., Matias, I., Martiadis, V., De Petrocellis, L., Maj, M., Di Marzo, V. Neuropsychopharmacology (2005) [Pubmed]
  9. Discovery of the Presence and Functional Expression of Cannabinoid CB2 Receptors in Brain. Onaivi, E.S., Ishiguro, H., Gong, J.P., Patel, S., Perchuk, A., Meozzi, P.A., Myers, L., Mora, Z., Tagliaferro, P., Gardner, E., Brusco, A., Akinshola, B.E., Liu, Q.R., Hope, B., Iwasaki, S., Arinami, T., Teasenfitz, L., Uhl, G.R. Ann. N. Y. Acad. Sci. (2006) [Pubmed]
  10. Role of endogenous cannabinoids in synaptic signaling. Freund, T.F., Katona, I., Piomelli, D. Physiol. Rev. (2003) [Pubmed]
  11. Pharmacology of cannabinoid receptors. Howlett, A.C. Annu. Rev. Pharmacol. Toxicol. (1995) [Pubmed]
  12. Differential expression of cannabinoid receptors in the human colon: cannabinoids promote epithelial wound healing. Wright, K., Rooney, N., Feeney, M., Tate, J., Robertson, D., Welham, M., Ward, S. Gastroenterology (2005) [Pubmed]
  13. 2-arachidonoylglycerol, an endogenous cannabinoid receptor ligand, induces rapid actin polymerization in HL-60 cells differentiated into macrophage-like cells. Gokoh, M., Kishimoto, S., Oka, S., Mori, M., Waku, K., Ishima, Y., Sugiura, T. Biochem. J. (2005) [Pubmed]
  14. The peripheral cannabinoid receptor: adenylate cyclase inhibition and G protein coupling. Bayewitch, M., Avidor-Reiss, T., Levy, R., Barg, J., Mechoulam, R., Vogel, Z. FEBS Lett. (1995) [Pubmed]
  15. Reduction of human monocytic cell neurotoxicity and cytokine secretion by ligands of the cannabinoid-type CB2 receptor. Klegeris, A., Bissonnette, C.J., McGeer, P.L. Br. J. Pharmacol. (2003) [Pubmed]
  16. Involvement of cannabinoid receptors in inflammatory hypersensitivity to colonic distension in rats. Sanson, M., Bueno, L., Fioramonti, J. Neurogastroenterol. Motil. (2006) [Pubmed]
  17. Functional heterogeneity in the antibodies produced to Borrelia burgdorferi. Benach, J.L. Wien. Klin. Wochenschr. (1999) [Pubmed]
  18. Cannabinoid receptor type 2 gene is associated with human osteoporosis. Karsak, M., Cohen-Solal, M., Freudenberg, J., Ostertag, A., Morieux, C., Kornak, U., Essig, J., Erxlebe, E., Bab, I., Kubisch, C., de Vernejoul, M.C., Zimmer, A. Hum. Mol. Genet. (2005) [Pubmed]
  19. The effects of cannabinoids on the brain. Ameri, A. Prog. Neurobiol. (1999) [Pubmed]
  20. Characterization of the endocannabinoid system in early human pregnancy. Helliwell, R.J., Chamley, L.W., Blake-Palmer, K., Mitchell, M.D., Wu, J., Kearn, C.S., Glass, M. J. Clin. Endocrinol. Metab. (2004) [Pubmed]
  21. Fatty acid amide hydrolase inhibitors from virtual screening of the endocannabinoid system. Saario, S.M., Poso, A., Juvonen, R.O., Järvinen, T., Salo-Ahen, O.M. J. Med. Chem. (2006) [Pubmed]
  22. Reduced endocannabinoid immune modulation by a common cannabinoid 2 (CB2) receptor gene polymorphism: possible risk for autoimmune disorders. Sipe, J.C., Arbour, N., Gerber, A., Beutler, E. J. Leukoc. Biol. (2005) [Pubmed]
  23. Distinct expression profiles of the peripheral cannabinoid receptor in lymphoid tissues depending on receptor activation status. Rayman, N., Lam, K.H., Laman, J.D., Simons, P.J., Löwenberg, B., Sonneveld, P., Delwel, R. J. Immunol. (2004) [Pubmed]
  24. Effects of Peripheral Cannabinoid Receptor Ligands on Motility and Polarization in Neutrophil-like HL60 Cells and Human Neutrophils. Kurihara, R., Tohyama, Y., Matsusaka, S., Naruse, H., Kinoshita, E., Tsujioka, T., Katsumata, Y., Yamamura, H. J. Biol. Chem. (2006) [Pubmed]
  25. Characterization of Peripheral Human Cannabinoid Receptor (hCB2) Expression and Pharmacology Using a Novel Radioligand, [35S]Sch225336. Gonsiorek, W., Hesk, D., Chen, S.C., Kinsley, D., Fine, J.S., Jackson, J.V., Bober, L.A., Deno, G., Bian, H., Fossetta, J., Lunn, C.A., Kozlowski, J.A., Lavey, B., Piwinski, J., Narula, S.K., Lundell, D.J., Hipkin, R.W. J. Biol. Chem. (2006) [Pubmed]
  26. Endocannabinoid 2-arachidonyl glycerol is a full agonist through human type 2 cannabinoid receptor: antagonism by anandamide. Gonsiorek, W., Lunn, C., Fan, X., Narula, S., Lundell, D., Hipkin, R.W. Mol. Pharmacol. (2000) [Pubmed]
  27. Role of a conserved lysine residue in the peripheral cannabinoid receptor (CB2): evidence for subtype specificity. Tao, Q., McAllister, S.D., Andreassi, J., Nowell, K.W., Cabral, G.A., Hurst, D.P., Bachtel, K., Ekman, M.C., Reggio, P.H., Abood, M.E. Mol. Pharmacol. (1999) [Pubmed]
  28. Novel cannabinol probes for CB1 and CB2 cannabinoid receptors. Mahadevan, A., Siegel, C., Martin, B.R., Abood, M.E., Beletskaya, I., Razdan, R.K. J. Med. Chem. (2000) [Pubmed]
  29. Activation of the human peripheral cannabinoid receptor results in inhibition of adenylyl cyclase. Slipetz, D.M., O'Neill, G.P., Favreau, L., Dufresne, C., Gallant, M., Gareau, Y., Guay, D., Labelle, M., Metters, K.M. Mol. Pharmacol. (1995) [Pubmed]
  30. Stimulation of cannabinoid receptor 2 (CB2) suppresses microglial activation. Ehrhart, J., Obregon, D., Mori, T., Hou, H., Sun, N., Bai, Y., Klein, T., Fernandez, F., Tan, J., Shytle, R.D. Journal of neuroinflammation [electronic resource]. (2005) [Pubmed]
  31. Autocrine and paracrine regulation of lymphocyte CB2 receptor expression by TGF-beta. Gardner, B., Zu, L.X., Sharma, S., Liu, Q., Makriyannis, A., Tashkin, D.P., Dubinett, S.M. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
  32. Fine mapping of the autosomal dominant juvenile open angle glaucoma (GLC1A) region and evaluation of candidate genes. Sunden, S.L., Alward, W.L., Nichols, B.E., Rokhlina, T.R., Nystuen, A., Stone, E.M., Sheffield, V.C. Genome Res. (1996) [Pubmed]
  33. First "hybrid" ligands of vanilloid TRPV1 and cannabinoid CB2 receptors and non-polyunsaturated fatty acid-derived CB2-selective ligands. Appendino, G., Cascio, M.G., Bacchiega, S., Moriello, A.S., Minassi, A., Thomas, A., Ross, R., Pertwee, R., De Petrocellis, L., Di Marzo, V. FEBS Lett. (2006) [Pubmed]
  34. p38 MAPK is involved in CB2 receptor-induced apoptosis of human leukaemia cells. Herrera, B., Carracedo, A., Diez-Zaera, M., Guzmán, M., Velasco, G. FEBS Lett. (2005) [Pubmed]
  35. 2-Arachidonoylglycerol, an endogenous cannabinoid receptor ligand, enhances the adhesion of HL-60 cells differentiated into macrophage-like cells and human peripheral blood monocytes. Gokoh, M., Kishimoto, S., Oka, S., Metani, Y., Sugiura, T. FEBS Lett. (2005) [Pubmed]
  36. Human brain endothelium: coexpression and function of vanilloid and endocannabinoid receptors. Golech, S.A., McCarron, R.M., Chen, Y., Bembry, J., Lenz, F., Mechoulam, R., Shohami, E., Spatz, M. Brain Res. Mol. Brain Res. (2004) [Pubmed]
  37. Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. Galiègue, S., Mary, S., Marchand, J., Dussossoy, D., Carrière, D., Carayon, P., Bouaboula, M., Shire, D., Le Fur, G., Casellas, P. Eur. J. Biochem. (1995) [Pubmed]
  38. Pharmacological actions of cannabinoids. Pertwee, R.G. Handbook of experimental pharmacology. (2005) [Pubmed]
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