Cannabinoid receptor type 2

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Cannabinoid receptor 2 (macrophage)
Protein CNR2 PDB 2KI9.png
Rendering based on PDB 2KI9.
Available structures
PDB Ortholog search: PDBe, RCSB
Symbols CNR2 ; CB-2; CB2; CX5
External IDs OMIM605051 MGI104650 HomoloGene1389 IUPHAR: 57 ChEMBL: 253 GeneCards: CNR2 Gene
RNA expression pattern
PBB GE CNR2 206586 at tn.png
More reference expression data
Species Human Mouse
Entrez 1269 12802
Ensembl ENSG00000188822 ENSMUSG00000062585
UniProt P34972 P47936
RefSeq (mRNA) NM_001841 NM_001305278
RefSeq (protein) NP_001832 NP_001292207
Location (UCSC) Chr 1:
23.87 – 23.91 Mb
Chr 4:
135.9 – 135.92 Mb
PubMed search [1] [2]

The cannabinoid receptor type 2, abbreviated as CB2, is a G protein-coupled receptor from the cannabinoid receptor family that in humans is encoded by the CNR2 gene.[1][2] It is closely related to the cannabinoid receptor type 1, which is largely responsible for the efficacy of endocannabinoid-mediated presynaptic-inhibition, the psychoactive properties of tetrahydrocannabinol, the active agent in marijuana, and other phytocannabinoids (natural cannabinoids).[1][3] The principal endogenous ligand for the CB2 receptor is 2-arachidonoylglycerol (2-AG).[2]

CB2 was cloned in 1993 by a research group from Cambridge looking for a second cannabinoid receptor that could explain the pharmacological properties of tetrahydrocannabinol.[1] The receptor was identified among cDNAs based on its similarity in amino-acid sequence to the cannabinoid receptor type 1 (CB1) receptor, discovered in 1990.[4] The discovery of this receptor helped provide a molecular explanation for the established effects of cannabinoids on the immune system.


The CB2 receptor is encoded by the CNR2 gene.[1][5] Approximately 360 amino acids comprise the human CB2 receptor, making it somewhat shorter than the 473-amino-acid-long CB1 receptor.[5]

As is commonly seen in G protein-coupled receptors, the CB2 receptor has seven transmembrane spanning domains,[6] a glycosylated N-terminus, and an intracellular C-terminus.[5] The C-terminus of CB2 receptors appears to play a critical role in the regulation of ligand-induced receptor desensitization and downregulation following repeated agonist application,[5] perhaps causing the receptor to become less responsive to particular ligands.

The human CB1 and the CB2 receptors possess approximately 44% amino acid similarity.[1] When only the transmembrane regions of the receptors are considered, however, the amino acid similarity between the two receptor subtypes is approximately 68%.[5] The amino acid sequence of the CB2 receptor is less highly conserved across human and rodent species as compared to the amino acid sequence of the CB1 receptor.[7] Based on computer modeling, ligand interactions with CB2 receptor residues S3.31 and F5.46 appears to determine differences between CB1 and CB2 receptor selectivity.[8] In CB2 receptors, lipophilic groups interact with the F5.46 residue, allowing them to form a hydrogen bond with the S3.31 residue.[8] These interactions induce a conformational change in the receptor structure, which triggers the activation of various intracellular signaling pathways. Further research is needed to determine the exact molecular mechanisms of signaling pathway activation.[8]


Like the CB1 receptors, CB2 receptors inhibit the activity of adenylyl cyclase through their Gi/Goα subunits.[9][10] Through their Gβγ subunits, CB2 receptors are also known to be coupled to the MAPK-ERK pathway,[9][10][11] a complex and highly conserved signal transduction pathway, which critically regulates a number of important cellular processes in both mature and developing tissues.[12] Activation of the MAPK-ERK pathway by CB2 receptor agonists acting through the Gβγ subunit ultimately results in changes in cell migration[13] as well as in an induction of the growth-related gene Zif268 (also known as Krox-24, NGFI-A, and egr-1).[11] The Zifi268 gene encodes a transcriptional regulator implicated in neuroplasticity and long term memory formation.[14]

At present, there are five recognized cannabinoids produced endogenously throughout the body: Arachidonoylethanolamine (anandamide), 2-arachidonoyl glycerol (2-AG), 2-arachidonyl glyceryl ether (noladin ether), virodhamine,[9] as well as the recently discovered N-arachidonoyl-dopamine (NADA).[15] Many of these ligands appear to exhibit properties of functional selectivity at the CB2 receptor: 2-AG preferentially activates the MAPK-ERK pathway, while noladin preferentially inhibits adenylyl cyclase.[9] Like noladin, the synthetic ligand CP-55,940 has also been shown to preferentially inhibit adenylyl cyclase in CB2 receptors.[9] Together, these results support the emerging concept of agonist-directed trafficking at the cannabinoid receptors.


Immune System[edit]

Initial investigation of CB2 receptor expression patterns focused on the presence of CB2 receptors in the peripheral tissues of the immune system [6] and found CB2 receptor mRNA is found throughout tissues of the spleen, tonsils, and thymus gland.[6] Northern blot analysis further indicates the expression of the CNR2 gene in immune tissues,[6] where they are primarily responsible for mediating cytokine release.[16] These receptors were primarily localized on immune cells such as monocytes, macrophages, B-cells, and T-cells.[2][6][17][18][19]


Further investigation into the expression patterns of the CB2 receptors revealed that CB2 receptor gene transcripts are also expressed in the brain, though not as densely as the CB1 receptor and located on different cells.[20] Unlike the CB1 receptor, in the brain, CB2 receptors are found primarily on microglia, but not neurons.[16][21] CB2Rs are expressed on some rat retinal cell types. [22]

Gastrointestinal System[edit]

CB2 receptors are also found throughout the gastrointestinal system, where they modulate intestinal inflammatory response.[23][24] Thus, CB2 receptor is a potential therapeutic target for inflammatory bowel diseases, such as Crohn's disease and ulcerative colitis.[24][25] The role of endocannabinoids, as such, play an important role in inhibiting unnecessary immune action upon the natural gut flora. Dysfunction of this system, perhaps from excess FAAH activity, could result in IBD. CB2 activation may also have a role in the treatment of irritable bowel syndrome.[26] Cannabinoid receptor agonists reduce gut motility in IBS patients.[27]

Peripheral Nervous System[edit]

Application of CB2-specific antagonists has found that these receptors are also involved in mediating analgesic effects in the peripheral nervous system. However, these receptors are not expressed by nociceptive sensory neurons, and at present are believed to exist on an undetermined, non-neuronal cell. Possible candidates include mast cells, known to facilitate the inflammatory response. Cannabinoid mediated inhibition of these responses may cause a decrease in the perception of noxious-stimuli.[4]


Immune System[edit]

Primary research on the functioning of the CB2 receptor has focused on the receptor's effects on the immunological activity of leukocytes.[28] To be specific, this receptor has been implicated in a variety of modulatory functions, including immune suppression, induction of apoptosis, and induction of cell migration.[2] Through their inhibition of adenylyl cyclase via their Gi/Goα subunits, CB2 receptor agonists cause a reduction in the intracellular levels of cyclic adenosine monophosphate (cAMP).[29][30] Although the exact role of the cAMP cascade in the regulation of immune responses is currently under debate, laboratories have previously demonstrated that inhibition of adenylyl cyclase by CB2 receptor agonists results in a reduction in the binding of transcription factor CREB (cAMP response element-binding protein) to DNA.[28] This reduction causes changes in the expression of critical immunoregulatory genes[29] and ultimately suppression of immune function.[30]

Later studies examining the effect of synthetic cannabinoid agonist JWH-015 on CB2 receptors revealed that changes in cAMP levels result in the phosphorylation of leukocyte receptor tyrosine kinase at Tyr-505, leading to an inhibition of T cell receptor signaling. Thus, CB2 agonists may also be useful for treatment of inflammation and pain, and are currently being investigated, in particular for forms of pain that do not respond well to conventional treatments, such as neuropathic pain.[31] Consistent with these findings are studies that demonstrate increased CB2 receptor expression in the spinal cord, dorsal root ganglion, and activated microglia in the rodent neuropathic pain model, as well as on human heptocellular carcinoma tumor samples.[32]

CB2 receptors have also been implicated in the regulation of homing and retention of marginal zone B cells. A study using knock-out mice found that CB2 receptor is essential for the maintenance of both MZ B cells and their precursor T2-MZP, though not their development. Both B cells and their precursors lacking this receptor were found in reduced numbers, explained by the secondary finding that 2-AG signaling was demonstrated to induce proper B cell migration to the MZ. Without the receptor, there was an undesirable spike in the blood concentration of MZ B lineage cells and a significant reduction in the production of IgM. While the mechanism behind this process is not fully understood, the researchers suggested that this process may be due to the activation-dependent decrease in cAMP concentration, leading to reduced transcription of genes regulated by CREB, indirectly increasing TCR signaling and IL-2 production.[2] Together, these findings demonstrate that the endocannabinoid system maybe exploited to enhance immunity to certain pathogens and autoimmune diseases.

Clinical Applications[edit]

CB2 receptors may have possible therapeutic roles in the treatment of neurodegenerative disorders such as Alzheimer's disease.[33][34] Specifically, the CB2 agonist JWH-015 was shown to induce macrophages to remove native beta-amyloid protein from frozen human tissues.[35] In patient's with Alzheimer's disease, beta-amyloid proteins form aggregates known as senile plaques, which disrupt neural functioning.[36]

Changes in endocannabinoid levels and/or CB2 receptor expressions have been reported in almost all diseases affecting humans,[37] ranging from cardiovascular, gastrointestinal, liver, kidney, neurodegenerative, psychiatric, bone, skin, autoimmune, lung disorders to pain and cancer. The prevalence of this trend suggests that modulating CB2 receptor activity by either selective CB2 receptor agonists or inverse agonists/antagonists depending on the disease and its progression holds unique therapeutic potential for these pathologies [37]

Modulation of cocaine reward[edit]

Researchers investigated the effects of CB2 agonists on cocaine self-administration in mice. Systemic administration of JWH-133 reduced the number of self-infusions of cocaine in mice, as well as reducing locomotor activity and the break point (maximum amount of level presses to obtain cocaine). Local injection of JWH-133 into the nucleus accumbens was found to produce the same effects as systemic administration. Systemic administration of JWH-133 also reduced basal and cocaine-induced elevations of extracellular dopamine in the nucleus accumbens. These findings were mimicked by another, structurally different CB2 agonist, GW-405,833, and were reversed by the administration of a CB2 antagonist, AM-630.[citation needed]


Many selective ligands for the CB2 receptor are now available.[38]

Partial agonists[edit]

Unspecified efficacy agonists[edit]


Inverse agonists[edit]

Binding affinities[edit]

CB1 affinity (Ki) Efficacy towards CB1 CB2 affinity (Ki) Efficacy towards CB2 Type References
Anandamide 78 nM Partial agonist 370 nM Partial agonist Endogenous
N-Arachidonoyl dopamine 250 nM Agonist 12000 nM  ? Endogenous [39]
2-Arachidonoylglycerol 58.3 nM Full agonist 145 nM Full agonist Endogenous [39]
2-Arachidonyl glyceryl ether 21 nM Full agonist 480 nM Full agonist Endogenous
Tetrahydrocannabinol 10 nM Partial agonist 24 nM Partial agonist Phytogenic [40][40]
EGCG 33.6 μM Agonist >50 μM  ? Phytogenic
AM-1221 52.3 nM Agonist 0.28 nM Agonist Synthetic [41]
AM-1235 1.5 nM Agonist 20.4 nM Agonist Synthetic [42]
AM-2232 0.28 nM Agonist 1.48 nM Agonist Synthetic [42]
UR-144 150 nM Full agonist 1.8 nM Full agonist Synthetic [43]
JWH-007 9.0 nM Agonist 2.94 nM Agonist Synthetic [44]
JWH-015 383 nM Agonist 13.8 nM Agonist Synthetic [44]
JWH-018 9.00 ± 5.00 nM Full agonist 2.94 ± 2.65 nM Full agonist Synthetic [45]

See also[edit]


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Further reading[edit]

  • Oddi S, Spagnuolo P, Bari M, D'Agostino A, Maccarrone M (2007). "Differential modulation of type 1 and type 2 cannabinoid receptors along the neuroimmune axis". International Review of Neurobiology. International Review of Neurobiology 82: 327–37. doi:10.1016/S0074-7742(07)82017-4. ISBN 978-0-12-373989-6. PMID 17678969. 
  • Galiègue S, Mary S, Marchand J, Dussossoy D, Carrière D, Carayon P, Bouaboula M, Shire D, Le Fur G, Casellas P (Aug 1995). "Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations". European Journal of Biochemistry / FEBS 232 (1): 54–61. doi:10.1111/j.1432-1033.1995.tb20780.x. PMID 7556170. 
  • Munro S, Thomas KL, Abu-Shaar M (Sep 1993). "Molecular characterization of a peripheral receptor for cannabinoids". Nature 365 (6441): 61–5. doi:10.1038/365061a0. PMID 7689702. 
  • Shire D, Calandra B, Rinaldi-Carmona M, Oustric D, Pessègue B, Bonnin-Cabanne O, Le Fur G, Caput D, Ferrara P (Jun 1996). "Molecular cloning, expression and function of the murine CB2 peripheral cannabinoid receptor". Biochimica Et Biophysica Acta 1307 (2): 132–6. doi:10.1016/0167-4781(96)00047-4. PMID 8679694. 
  • Tao Q, McAllister SD, Andreassi J, Nowell KW, Cabral GA, Hurst DP, Bachtel K, Ekman MC, Reggio PH, Abood ME (Mar 1999). "Role of a conserved lysine residue in the peripheral cannabinoid receptor (CB2): evidence for subtype specificity". Molecular Pharmacology 55 (3): 605–13. PMID 10051546. 
  • Nong L, Newton C, Friedman H, Klein TW (2002). "CB1 and CB2 receptor mRNA expression in human peripheral blood mononuclear cells (PBMC) from various donor types". Advances in Experimental Medicine and Biology. Advances in Experimental Medicine and Biology 493: 229–33. doi:10.1007/0-306-47611-8_27. ISBN 0-306-46466-7. PMID 11727770.  |chapter= ignored (help)
  • Ho BY, Current L, Drewett JG (Jul 2002). "Role of intracellular loops of cannabinoid CB(1) receptor in functional interaction with G(alpha16)". FEBS Letters 522 (1-3): 130–4. doi:10.1016/S0014-5793(02)02917-4. PMID 12095632. 
  • Matias I, Pochard P, Orlando P, Salzet M, Pestel J, Di Marzo V (Aug 2002). "Presence and regulation of the endocannabinoid system in human dendritic cells". European Journal of Biochemistry / FEBS 269 (15): 3771–8. doi:10.1046/j.1432-1033.2002.03078.x. PMID 12153574. 
  • Song ZH, Feng W (Nov 2002). "Absence of a conserved proline and presence of a conserved tyrosine in the CB2 cannabinoid receptor are crucial for its function". FEBS Letters 531 (2): 290–4. doi:10.1016/S0014-5793(02)03537-8. PMID 12417328. 
  • Casanova ML, Blázquez C, Martínez-Palacio J, Villanueva C, Fernández-Aceñero MJ, Huffman JW, Jorcano JL, Guzmán M (Jan 2003). "Inhibition of skin tumor growth and angiogenesis in vivo by activation of cannabinoid receptors". The Journal of Clinical Investigation 111 (1): 43–50. doi:10.1172/JCI16116. PMC 151833. PMID 12511587. 
  • Feng W, Song ZH (Apr 2003). "Effects of D3.49A, R3.50A, and A6.34E mutations on ligand binding and activation of the cannabinoid-2 (CB2) receptor". Biochemical Pharmacology 65 (7): 1077–85. doi:10.1016/S0006-2952(03)00005-4. PMID 12663043. 
  • Kishimoto S, Gokoh M, Oka S, Muramatsu M, Kajiwara T, Waku K, Sugiura T (Jul 2003). "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". The Journal of Biological Chemistry 278 (27): 24469–75. doi:10.1074/jbc.M301359200. PMID 12711605. 
  • Jorda MA, Rayman N, Valk P, De Wee E, Delwel R (May 2003). "Identification, characterization, and function of a novel oncogene: the peripheral cannabinoid receptor Cb2". Annals of the New York Academy of Sciences 996: 10–6. doi:10.1111/j.1749-6632.2003.tb03227.x. PMID 12799277. 
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This article incorporates text from the United States National Library of Medicine, which is in the public domain.