Cannabinoid receptor type 2

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Cannabinoid receptor 2 (macrophage)
Identifiers
SymbolsCNR2; CB2; CX5
External IDsOMIM: 605051 MGI: 104650 HomoloGene: 1389 IUPHAR: CB2 GeneCards: CNR2 Gene
RNA expression pattern
250px
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez126912802
EnsemblENSG00000188822ENSMUSG00000062585
UniProtP34972Q544H5
RefSeq (mRNA)NM_001841NM_009924
RefSeq (protein)NP_001832NP_034054
Location (UCSC)Chr 1:
24.07 - 24.11 Mb		Chr 4:
135.17 - 135.19 Mb
PubMed search[1][2]

Cannabinoid receptor 2 (macrophage), also known as CB2 or CNR2, is a G protein-coupled receptor from the cannabinoid receptor family, which in humans is encoded by the CNR2 gene.[1] It is closely related to the cannabinoid receptor 1 which is responsible for the psychoactive properties of tetrahydrocannabinol, the active principle of marijuana.[1][2]

History

CB2 was cloned in 1993 by a research group from Cambridge looking for a second cannabinoid receptor which could explain the pharmacological properties of tetrahydrocannabinol, the active principle of marijuana.[1]

Signaling

Like the CB1 receptors, CB2 receptors inhibit the activity of adenylyl cyclase through their Gi/Goα subunits.[3][4] Through their Gβγ subunits, CB2 receptors are also known to be coupled to the MAPK/ERK pathway[3][4][5], a complex and highly conserved signal transduction pathway, which critically regulates a number of important cellular processes in both mature and developing tissues.[6] Activation of the MAPK-ERK pathway by CB2 receptor agonists acting on the Gβγ receptor subunit ultimately results in changes in cell migration[7] as well as in an induction of the growth-related gene Zif268(also known as Krox-24, NGFI-A, and egr-1)[5] The Zifi268 gene encodes a transcriptional regulator implicated in neuroplasticity and long term memory formation.[8]

At present, there are five recognized cannabinoids which are produced endogenously throughout the body; these endocannabinoids include Arachidonoylethanolamine (anandamide), 2-arachidonoyl glycerol (2-AG), 2-arachidonyl glyceryl ether (noladin ether), virodhamine,[3] as well as the recently-discovered N-arachidonoyl-dopamine (NADA).[9] 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[3]. Like noladin, the synthetic ligand CP-55,940 has also been shown to preferentially inhibit adenylyl cyclase in CB2 receptors.[3] Similar ligand-specific signaling has also been demonstrated in the CB1 receptor.[10] Together, these results support the emerging concept of agonist-directed trafficking at the cannabinoid receptors.

Structure

The CB2 receptor is encoded by the CNR2 gene.[1][11] Approximately 360 amino acids comprise the human CB2 receptor, making it somewhat shorter than the 473 amino acid long CB1 receptor.[11] As is commonly seen in G protein-coupled receptors, the CB2 receptor has seven transmembrane spanning domains.[12] The CB2 receptor also contains a glycosylated N-terminus as well as an intracellular C-terminus.[11] The C-terminus of CB2 receptors appears to play a critical role in the regulation of ligand-induced receptor desensitization and downregulation;[11] as a result of these processes, the cell may become less responsive to particular ligands.

The human CB1 and the CB2 receptors share approximately 44% amino acid similarity.[1] When only the transmembrane regions of the receptors are considered, however, the amino acid similarly between the two receptor subtypes is approximately 68%.[11] 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.[13] Based on computer modeling, ligand interactions with CB2 receptor residues S3.31 and F5.46 appears to determine differences in CB1 vs CB2 receptor selectivity.[14] In CB2 receptors, lipophilic groups interact with the F5.46 residue, allowing them to form a hydrogen bond with the S3.31 residue.[14] Ultimately, these interactions induce a conformational change in the receptor structure, activating various intracellular signaling pathways. Further research is needed to determine the exact molecular mechanisms of signaling pathway activation, however.[14]

Expression profile

Initial investigation of CB2 receptor expression patterns focused on the presence of CB2 receptors in the peripheral tissues of the immune system.[12] For instance, CB2 receptor mRNA was found throughout the immune tissues of the spleen, tonsils and thymus gland.[12] Northern blot analysis further indicates the expression of the CNR2 gene in immune tissues.[12] These receptors were primarily localized on immune cells such as monocytes, macrophages, B-cells, and T-cells.[12][15][16][17] Further investigation into the expression patterns of the CB2 receptors revealed that CB2 receptor gene transcripts are also widely distributed throughout the brain.[18] The CB2 receptors are found primarily on microglia(the immune cells of the CNS) and not neurons, however.[19] CB2 receptors are also found throughout the gastrointestinal system, where they modulate intestinal inflammatory response.[20] [21] Thus, CB2 receptor agonists are a potential therapeutic target for inflammatory bowel diseases, such as Crohn’s disease and ulcerative colitis.[21][22]

Functions and Clinical Applications

Primary research on the functioning of the CB2 receptor has focused on the receptor's effects on the immunological activity of leukocytes.[23] 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).[24][25] 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 transcription factor CREB (cAMP response element binding protein) binding to DNA[23]; this in turn causes changes in the expression of critical immunoregulatory genes,[24] and ultimately a suppression of immune function.[25] Later studies examining the effect of synthetic cannabinoid agonist JWH-015 on CB2 receptors revealed that changes in cAMP levels resulted in the phosphorylation of leukocyte receptor tyrosine kinase at Tyr-505; through this mechanism, T cell receptor signaling was inhibited. These results further demonstrate the immunosuppressive properties of CB2 receptor agonists. Thus, CB2 agonists may also be useful for treatment of inflammation and pain, and they are currently being investigated particularly for forms of pain that do not respond well to conventional treatments, such as neuropathic pain.[26]

CB2 receptors may have possible therapeutic roles in the treatment of neurodegenerative disorders such as Alzheimer's disease.[27][28]. Specifically, the CB2 agonist JWH-015 was shown to induce macrophages to remove native beta-amyloid protein from frozen human tissues.[29] In patient's with Alzheimer's disease, beta-amyloid proteins form aggregates known as senile plaques, which disrupt neural functioning.[30]

Selective Ligands

Many selective ligands for the CB2 receptor are now available.[31]

Agonists

Antagonists and inverse agonists

See also

References

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External links

Further reading

This article incorporates text from the United States National Library of Medicine, which is in the public domain.


Class A: Rhodopsin like
α1 (A, B, D) · α2 (A, B, C) · β1 · β2 · β3
Adenosine (A1, A2A, A2B, A3) · P2Y (1, 2, 4, 5, 6, 8, 9, 10, 11, 12, 13, 14)
(all but 5-HT3) 5-HT1 (A, B, D, E, F) · 5-HT2 (A, B, C) · 5-HT (4, 5A, 6, 7)
Other
Acetylcholine (M1, M2, M3, M4, M5) · Dopamine (D1, D2, D3, D4, D5) · Histamine (H1, H2, H3, H4) · Melatonin (1A, 1B, 1C) · TAAR (1, 2, 3, 5, 6, 8, 9)
Metabolites and
signaling molecules
CysLT (1, 2) · LTB4 (1, 2) · FPRL1 · OXE · Prostaglandin (DP (1, 2), EP (1, 2, 3, 4), FP) · Prostacyclin · Thromboxane
Other
Bile acid · Cannabinoid (CB1, CB2, GPR (18, 55, 119)) · EBI2 · Estrogen · Free fatty acid (1, 2, 3, 4) · Lactate  · Lysophosphatidic acid (1, 2, 3, 4, 5, 6)  · Lysophospholipid (1, 2, 3, 4, 5, 6, 7, 8) · Niacin (1, 2) · Oxoglutarate · PAF · Sphingosine-1-phosphate (1, 2, 3, 4, 5) · Succinate
Peptide
B/W (1, 2) · FF (1, 2) · S · Y (1, 2, 4, 5) · Neuromedin (B, U (1, 2)) · Neurotensin (1, 2)
Other
Miscellaneous
GPR (1, 3, 4, 6, 12, 15, 17, 18, 19, 20, 21, 22, 23, 25, 26, 27, 31, 32, 33, 34, 35, 37, 39, 42, 44, 45, 50, 52, 55, 61, 62, 63, 65, 68, 75, 77, 78, 81, 82, 83, 84, 85, 87, 88, 92, 101, 103, 109A, 109B, 119, 120, 132, 135, 137B, 139, 141, 142, 146, 148, 149, 150, 151, 152, 153, 160, 161, 162, 171, 173, 174, 176, 177, 182, 183)
Other
Class B: Secretin like
GPR (56, 64, 97, 98, 110, 111, 112, 113, 114, 115, 116, 123, 124, 125, 126, 128, 133, 143, 144, 155, 157)
Other
Class C: Metabotropic
glutamate / pheromone
TAS1R (1, 2, 3) · TAS2R (1, 3, 4, 5, 8, 9, 10, 12, 13, 14, 16, 19, 20, 30, 31, 38, 39, 40, 41, 42, 43, 45, 46, 50)
Other
Class F:
Frizzled / Smoothened
Frizzled
Frizzled (1, 2, 3, 4, 5, 6, 7, 8, 9, 10)
Smoothened
  1. ↑ 1.0 1.1 1.2 1.3 1.4 Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  2. ↑ "Entrez Gene: CNR2 cannabinoid receptor 2 (macrophage)". 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 Shoemaker JL, Ruckle MB, Mayeux PR, Prather PL (2005). "Agonist-Directed Trafficking of Response by Endocannabinoids Acting at CB2 Receptors". J Pharmacol Exp Ther. 315 (2): 828–838. doi:10.1124/jpet.105.089474. PMID 16081674. 
  4. ↑ 4.0 4.1 Demuth DG, Molleman A. (2006). "Cannabinoid Signalling". Life Sci. 78 (6): 549–563. doi:10.1016/j.lfs.2005.05.055. PMID 16109430. 
  5. ↑ 5.0 5.1 Bouaboula M, Poinot-Chazel C, Marchand J, Canat X, Bourrié B, Rinaldi-Carmona M, Calandra B, Le Fur G, Casellas P. (19966). "Signaling pathway associated with stimulation of CB2 peripheral cannabinoid receptor. Involvement of both mitogen-activated protein kinase and induction of Krox-24 expression". Eur J Biochem. 237 (3): 704–711. doi:10.1111/j.1432-1033.1996.0704p.x. PMID 8647116.  Check date values in: |date= (help)
  6. ↑ Shvartsman SY, Coppey M, Berezhkovskii AM (2009). "MAPK signaling in equations and embryos". Fly (Austin). 3 (1): 62–7. PMC 2712890 Freely accessible. PMID 19182542. 
  7. ↑ Klemke RL, Cai S, Gianni AL, Gallagher PJ, Lanerolle P, Cheresh DA. (1997). "Regulation of Cell Motility by Mitogen-activated Protein Kinase". J Cell Bio. 137 (2): 481–492. doi:10.1083/jcb.137.2.481. PMC 2139771 Freely accessible. PMID 9128257. 
  8. ↑ Alberini CM. (2009). "Transcription factors in long-term memory and synaptic plasticity". Physiol Rev. 89 (1): 121–145. doi:10.1152/physrev.00017.2008. PMID 19126756. 
  9. ↑ Bisogno, T., D. Melck, M. Bobrov, N. M. Gretskaya, V. V. Bezuglov, L. De Petrocellis, V. Di Marzo. "N-acyl-dopamines: novel synthetic CB1 cannabinoid-receptor ligands and inhibitors of anandamide inactivation with cannabimimetic activity in vitro and in vivo." The Biochemical Journal. 2000 Nov 1;351 Pt 3:817-24. PMID 11042139
  10. ↑ Bonhaus DW, Chang LK, Kwan, Martin GR G. R. (1998). "Dual Activation and Inhibition of Adenylyl Cyclase by Cannabinoid Receptor Agonists: Evidence for Agonist-Specific Trafficking of Intracellular Responses". J Pharmacol Exp Ther. 287 (3): 884–8. PMID 9864268. 
  11. ↑ 11.0 11.1 11.2 11.3 11.4 Cabral GA, Griffin-Thomas L. (2009). "Emerging role of the cannabinoid receptor CB2 in immune regulation: therapeutic prospects for neuroinflammation". Expert Rev Mol Med. 11: e3. doi:10.1017/S1462399409000957. PMC 2768535 Freely accessible. PMID 19152719. 
  12. ↑ 12.0 12.1 12.2 12.3 12.4 Sylvaine G, Sophie M, Marchand J, Dussossoy D, Carriere D, Carayon P, Monsif B, Shire D, LE Fur G, Casellas P (1995). "Expression of Central and Peripheral Cannabinoid Receptors in Human Immune Tissues and Leukocyte Subpopulations". Eur J Biochem. 232 (1): 54–61. doi:10.1111/j.1432-1033.1995.tb20780.x. PMID 7556170. 
  13. ↑ Griffin G, Tao Q, Abood ME (2000). "Cloning and pharmacological characterization of the rat CB(2) cannabinoid receptor". J Pharmacol Exp Ther. 292 (3): 886–894. PMID 10688601. 
  14. ↑ 14.0 14.1 14.2 Tuccinardi T, Ferrarini PL, Manera C, Ortore G, Saccomanni G, Martinelli A. (2006). "Cannabinoid CB2/CB1 selectivity. Receptor modeling and automated docking analysis". J Med Chem. 49 (3): 984–994. doi:10.1021/jm050875u. PMID 16451064. 
  15. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  16. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  17. ↑ Centonze D, Battistini L, Maccarrone M (2008). "The endocannabinoid system in peripheral lymphocytes as a mirror of neuroinflammatory diseases". Curr. Pharm. Des. 14 (23): 2370–42. doi:10.2174/138161208785740018. PMID 18781987. 
  18. ↑ Onaivi ES (2006). "Neuropsychobiological evidence for the functional presence and expression of cannabinoid CB2 receptors in the brain". Neuropsychobiology. 54 (4): 231–46. doi:10.1159/000100778. PMID 17356307. 
  19. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  20. ↑ Izzo AA. (2004). "Cannabinoids and intestinal motility: welcome to CB2 receptors". Br J Pharmacol. 142 (8): 1247–54. doi:10.1038/sj.bjp.0705890. PMC 1575197 Freely accessible. PMID 15277313. 
  21. ↑ 21.0 21.1 Wright KL, Duncan M, Sharkey KA. (2008). "Cannabinoid CB2 receptors in the gastrointestinal tract: a regulatory system in states of inflammation". Br J Pharmacol. 153 (2): 263–70. doi:10.1038/sj.bjp.0707486. PMC 2219529 Freely accessible. PMID 17906675. 
  22. ↑ Capasso R, Borrelli F, Aviello G, Romano B, Scalisi C, Capasso F, Izzo AA. (2008). "Cannabidiol, extracted from Cannabis sativa, selectively inhibits inflammatory hypermotility in mice". Br J Pharmacol. 154 (5): 1001–8. doi:10.1038/bjp.2008.177. PMC 2451037 Freely accessible. PMID 18469842. 
  23. ↑ 23.0 23.1 Kaminski NE. (1998). "Inhibition of the cAMP signaling cascade via cannabinoid receptors: a putative mechanism of immune modulation by cannabinoid compounds". Toxicol Lett. 102-103: 59–63. doi:10.1016/S0378-4274(98)00284-7. PMID 10022233. 
  24. ↑ 24.0 24.1 Herring AC, Koh WS, Kaminski NE. (1998). "Inhibition of the cyclic AMP signaling cascade and nuclear factor binding to CRE and kappaB elements by cannabinol, a minimally CNS-active cannabinoid". Biochem Pharmacol. 55 (7): 1013–23. doi:10.1016/S0006-2952(97)00630-8. PMID 9605425. 
  25. ↑ 25.0 25.1 Kaminski NE. (1996). "Immune regulation by cannabinoid compounds through the inhibition of the cyclic AMP signaling cascade and altered gene expression". Biochem Pharmacol. 52 (8): 1133–40. doi:10.1016/0006-2952(96)00480-7. PMID 8937419. 
  26. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  27. ↑ Benito C, Núñez E, Tolón RM; et al. (2003). "Cannabinoid CB2 receptors and fatty acid amide hydrolase are selectively overexpressed in neuritic plaque-associated glia in Alzheimer's disease brains". J. Neurosci. 23 (35): 11136–41. PMID 14657172. 
  28. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  29. ↑ Tolón RM, Núñez E, Pazos MR, Benito C, Castillo AI, Martínez-Orgado JA, Romero J. (2009). "The activation of cannabinoid CB2 receptors stimulates in situ and in vitro beta-amyloid removal by human macrophages". Brain Res. 62 (11): 1984–9. doi:10.1016/j.brainres.2009.05.098. PMID 19505450. 
  30. ↑ Tiraboschi P, Hansen LA, Thal LJ, Corey-Bloom J. (2004). "The importance of neuritic plaques and tangles to the development and evolution of AD". Neurology. 62 (11): 1984–9. PMID 15184601. 
  31. ↑ Marriott KS, Huffman JW (2008). "Recent advances in the development of selective ligands for the cannabinoid CB(2) receptor". Curr Top Med Chem. 8 (3): 187–204. doi:10.2174/156802608783498014. PMID 18289088. 
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