Alternative titles; symbols
HGNC Approved Gene Symbol: CNR2
Cytogenetic location: 1p36.11 Genomic coordinates (GRCh38): 1:23,870,515-23,913,362 (from NCBI)
In addition to its renowned psychoactive properties, marijuana, or its major active cannabinoid ingredient, delta-9-tetrahydrocannabinol, exerts analgesic, antiinflammatory, immunosuppressive, anticonvulsive, and antiemetic effects as well as the alleviation of intraocular pressure in glaucoma. The G protein-coupled cannabinoid receptor-1 (CNR1; 114610), which is expressed in brain but not in the periphery, apart from low levels in testis, does not readily account for the nonpsychoactive effects of cannabinoids. Using PCR with degenerate primers to screen a promyelocytic leukemia cell cDNA library, Munro et al. (1993) obtained a cDNA encoding CNR2, which the authors called CX5. Sequence analysis predicted that the deduced 360-amino acid 7-transmembrane-spanning protein has 44% amino acid identity with CNR1 overall and 68% identity with the transmembrane residues proposed to confer ligand specificity. Binding analysis determined than CNR2 encodes a high-affinity receptor for cannabinoids, with higher affinity than CNR1 for cannabinol. Northern blot analysis revealed that the expression of 2.5- and 5.0-kb transcripts in the HL60 myeloid cell line increases on myeloid, or granulocyte, differentiation. Using the rat CX5 homolog, Munro et al. (1993) found that the 2.5-kb transcript is expressed in spleen but not in brain, kidney, lung, thymus, liver, or nasal epithelium. In situ hybridization analysis demonstrated expression in splenic marginal zones. PCR analysis detected CNR2 expression in purified splenic macrophages but not in CD5+ T cells. Munro et al. (1993) speculated that the location of CNR2 suggests that its endogenous ligand should have an immunomodulatory role.
Karsak et al. (2005) stated that the CNR2 gene maps to chromosome 1p36.
The International Radiation Hybrid Mapping Consortium mapped the CNR2 gene to chromosome 1 (stSG90).
Van Sickle et al. (2005) reported the expression of CB2 receptor mRNA and protein localization on brainstem neurons. These functional CB2 receptors in the brainstem were activated by a CB2 receptor agonist, 2-arachidonoylglycerol, and by elevated endogenous levels of endocannabinoids, which also act at CB1 receptors. Van Sickle et al. (2005) concluded that CB2 receptors represent an alternative site of action of endocannabinoids that opens the possibility of nonpsychotropic therapeutic interventions using enhanced endocannabinoid levels in localized brain areas.
By real-time RT-PCR of mouse diaphyseal bone marrow-derived stromal cells, Ofek et al. (2006) found that Cb2 expression progressively increased during osteoblastic differentiation in parallel with the expression of osteoblastic marker genes. Immunohistochemical analysis of distal femoral metaphyseal sections showed Cb2 in osteoblasts, osteocytes, and osteoclasts. A CB2-specific agonist without psychotropic effects enhanced endocortical osteoblast number and activity and restrained trabecular osteoclastogenesis by inhibiting proliferation of osteoclast precursors and Rankl (602642) expression in bone marrow-derived osteoblasts/stromal cells. The same agonist attenuated ovariectomy-induced bone loss and stimulated cortical thickness by suppressing osteoclast number and stimulating endocortical bone formation.
For discussion of a possible association between variation in the CNR2 gene and bone mineral density, see BMND3 (606928).
Steffens et al. (2005) investigated the effects of THC in a mouse model of established atherosclerosis. Oral administration of THC (1 mg/kg(-1) per day) resulted in significant inhibition of disease progression. This effective dose is lower than the dose usually associated with psychotropic effects of THC. Furthermore, Steffens et al. (2005) detected CB2 receptor (the main cannabinoid receptor expressed on immune cells) in both human and mouse atherosclerotic plaques. Lymphoid cells isolated from THC-treated mice showed diminished proliferation capacity and decreased interferon-gamma (147570) secretion. Macrophage chemotaxis, which is a crucial step for the development of atherosclerosis, was also inhibited in vitro by THC. All these effects were completely blocked by a specific CB2 receptor antagonist. Steffens et al. (2005) concluded that oral treatment with a low dose of THC inhibited atherosclerosis progression in the apolipoprotein E (107741) knockout mouse model, through pleiotropic immunomodulatory effects on lymphoid and myeloid cells, and that THC or cannabinoids with activity at the CB2 receptor may be valuable targets for treating atherosclerosis.
Ofek et al. (2006) found Cb2 -/- mice were healthy, fertile, and of size and weight indistinguishable from age-matched wildtype controls. However, both male and female Cb2 -/- mice had low bone mass due to accelerated age-related trabecular bone loss and cortical expansion, although cortical thickness remained unaltered. There was also increased activity of trabecular osteoblasts, increased osteoclast number, and markedly decreased number of diaphyseal osteoblast precursors. Ofek et al. (2006) concluded that CB2 is essential for the maintenance of normal bone mass.
Rousseaux et al. (2007) found that the probiotic bacterial strain Lactobacillus acidophilus NCFM induced a sustained increase of opioid receptor mu-1 (OPRM1; 600018) and CNR2 mRNA expression in human intestinal epithelial cells. In vivo experiments in mice and rats revealed that oral administration of L. bacillus NCFM induced colonic expression of OPRM1 and CNR2 and, in studies in rats, decreased normal visceral perception with a 20% increase in the pain threshold as elicited by colorectal distention. In a rat model of chronic colonic hypersensitivity that mimics irritable bowel syndrome, oral administration of NCFM resulted in an antinociceptive effect of the same magnitude as that caused by the subcutaneous administration of 1 mg per kg of morphine. NCFM-induced analgesia was significantly inhibited by peritoneal administration of a CNR2-selective antagonist but not by an opioid receptor antagonist. Rousseaux et al. (2007) concluded that direct contact of NCFM with epithelial cells can induce OPRM1 and CNR2 expression and can contribute to modulation and restoration of the normal perception of visceral pain.
In an animal model for cutaneous contact hypersensitivity, Karsak et al. (2007) found that mice lacking both known cannabinoid receptors displayed exacerbated allergic inflammation. In contrast, fatty acid amide hydrolase (FAAH; 602935)-deficient mice, which have increased levels of endocannabinoid anandamide, displayed reduced allergic responses in the skin. Cannabinoid receptor antagonists exacerbated allergic inflammation, whereas receptor agonists attenuated inflammation. Karsak et al. (2007) concluded that their results demonstrated a protective role of the endocannabinoid system in contact allergy in the skin and suggested a target for therapeutic intervention.
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. Cannabinoid receptor type 2 gene is associated with human osteoporosis. Hum. Molec. Genet. 14: 3389-3396, 2005. [PubMed: 16204352] [Full Text: https://doi.org/10.1093/hmg/ddi370]
Karsak, M., Gaffal, E., Date, R., Wang-Eckhardt, L., Rehnelt, J., Petrosino, S., Starowicz, K., Steuder, R., Schlicker, E., Cravatt, B., Mechoulam, R., Buettner, R., Werner, S., Di Marzo, V., Tuting, T., Zimmer, A. Attenuation of allergic contact dermatitis through the endocannabinoid system. Science 316: 1494-1497, 2007. [PubMed: 17556587] [Full Text: https://doi.org/10.1126/science.1142265]
Munro, S., Thomas, K. L., Abu-Shaar, M. Molecular characterization of a peripheral receptor for cannabinoids. Nature 365: 61-65, 1993. [PubMed: 7689702] [Full Text: https://doi.org/10.1038/365061a0]
Ofek, O., Karsak, M., Leclerc, N., Fogel, M., Frenkel, B., Wright, K., Tam, J., Attar-Namdar, M., Kram, V., Shohami, E., Mechoulam, R., Zimmer, A., Bab, I. Peripheral cannabinoid receptor, CB2, regulates bone mass. Proc. Nat. Acad. Sci. 103: 696-701, 2006. [PubMed: 16407142] [Full Text: https://doi.org/10.1073/pnas.0504187103]
Rousseaux, C., Thuru, X., Gelot, A., Barnich, N., Neut, C., Dubuquoy, L., Dubuquoy, C., Merour, E., Geboes, K., Chamaillard, M., Ouwehand, A., Leyer, G., Carcano, D., Colombel, J.-F., Ardid, D., Desreumaux, P. Lactobacillus acidophilus modulates intestinal pain and induces opioid and cannabinoid receptors. Nature Med. 13: 35-37, 2007. [PubMed: 17159985] [Full Text: https://doi.org/10.1038/nm1521]
Steffens, S., Veillard, N. R., Arnaud, C., Pelli, G., Burger, F., Staub, C., Karsak, M., Zimmer, A., Frossard, J.-L., Mach, F. Low dose oral cannabinoid therapy reduces progression of atherosclerosis in mice. Nature 434: 782-786, 2005. Note: Erratum: Nature 435: 528 only, 2005. [PubMed: 15815632] [Full Text: https://doi.org/10.1038/nature03389]
Van Sickle, M. D., Duncan, M., Kingsley, P. J., Mouihate, A., Urbani, P., Mackie, K., Stella, N., Makriyannis, A., Piomelli, D., Davison, J. S., Marnett, L. J., Di Marzo, V., Pittman, Q. J., Patel, K. D., Sharkey, K. A. Identification and functional characterization of brainstem cannabinoid CB2 receptors. Science 310: 329-332, 2005. [PubMed: 16224028] [Full Text: https://doi.org/10.1126/science.1115740]