View source for Cannabinoid receptor 2

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{{Short description|Mammalian protein found in Homo sapiens}}
{{redirect|CNR2|the airport in Ontario, Canada|Innerkip Aerodrome}}
{{Infobox_gene}}
The '''cannabinoid receptor 2''' '''(CB2)''', is a [[G protein-coupled receptor]] from the [[cannabinoid receptor]] family that in humans is encoded by the ''CNR2'' gene.<ref name="pmid7689702"/><ref name="pmid22048769">{{cite journal | vauthors = Basu S, Ray A, Dittel BN | title = Cannabinoid receptor 2 is critical for the homing and retention of marginal zone B lineage cells and for efficient T-independent immune responses | journal = Journal of Immunology | volume = 187 | issue = 11 | pages = 5720–5732 | date = December 2011 | pmid = 22048769 | pmc = 3226756 | doi = 10.4049/jimmunol.1102195 }}</ref>  It is closely related to the [[cannabinoid receptor 1]] (CB1), which is largely responsible for the efficacy of endocannabinoid-mediated presynaptic-inhibition, the psychoactive properties of [[tetrahydrocannabinol]] (THC), the active agent in [[cannabis]], and other [[phytocannabinoid]]s (plant cannabinoids).<ref name="pmid7689702">{{cite journal | vauthors = Munro S, Thomas KL, Abu-Shaar M | title = Molecular characterization of a peripheral receptor for cannabinoids | journal = Nature | volume = 365 | issue = 6441 | pages = 61–65 | date = September 1993 | pmid = 7689702 | doi = 10.1038/365061a0 | s2cid = 4349125 | bibcode = 1993Natur.365...61M }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: CNR2 cannabinoid receptor 2 (macrophage)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1269}}</ref> The principal endogenous ligand for the CB2 receptor is [[2-Arachidonoylglycerol]] (2-AG).<ref name="pmid22048769"/>
CB2 was [[cloning|cloned]] in 1993 by a research group from Cambridge looking for a second cannabinoid receptor that could explain the pharmacological properties of [[tetrahydrocannabinol]].<ref name="pmid7689702"/> The receptor was identified among [[cDNA]]s based on its similarity in amino-acid sequence to the cannabinoid receptor 1 (CB1) receptor, discovered in 1990.<ref name="pmid11316486">{{cite journal | vauthors = Elphick MR, Egertová M | title = The neurobiology and evolution of cannabinoid signalling | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 356 | issue = 1407 | pages = 381–408 | date = March 2001 | pmid = 11316486 | pmc = 1088434 | doi = 10.1098/rstb.2000.0787 }}</ref> The discovery of this receptor helped provide a molecular explanation for the established effects of cannabinoids on the immune system.
== Structure ==
The CB2 receptor is encoded by the ''CNR2'' gene.<ref name="pmid7689702"/><ref name="pmid19152719">{{cite journal | vauthors = Cabral GA, Griffin-Thomas L | title = Emerging role of the cannabinoid receptor CB2 in immune regulation: therapeutic prospects for neuroinflammation | journal = Expert Reviews in Molecular Medicine | volume = 11 | pages = e3 | date = January 2009 | pmid = 19152719 | pmc = 2768535 | doi = 10.1017/S1462399409000957 }}</ref>  Approximately 360 [[amino acids]] comprise the human CB2 receptor, making it somewhat shorter than the 473-amino-acid-long CB1 receptor.<ref name="pmid19152719"/>
As is commonly seen in G protein-coupled receptors, the CB2 receptor has seven transmembrane spanning domains,<ref name="pmid7556170">{{cite journal | vauthors = Galiègue S, Mary S, Marchand J, Dussossoy D, Carrière D, Carayon P, Bouaboula M, Shire D, Le Fur G, Casellas P | display-authors = 6 | title = Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations | journal = European Journal of Biochemistry | volume = 232 | issue = 1 | pages = 54–61 | date = August 1995 | pmid = 7556170 | doi = 10.1111/j.1432-1033.1995.tb20780.x | doi-access = free }}</ref> a glycosylated [[N-terminus]], and an intracellular [[C-terminus]].<ref name="pmid19152719"/>  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,<ref name="pmid19152719"/> perhaps causing the receptor to become less responsive to particular ligands.
The human CB1 and the CB2 receptors possess approximately 44% amino acid similarity.<ref name="pmid7689702" /> When only the transmembrane regions of the receptors are considered, however, the amino acid similarity between the two receptor subtypes is approximately 68%.<ref name="pmid19152719"/>  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.<ref name="pmid10688601">{{cite journal | vauthors = Griffin G, Tao Q, Abood ME | title = Cloning and pharmacological characterization of the rat CB(2) cannabinoid receptor | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 292 | issue = 3 | pages = 886–894 | date = March 2000 | pmid = 10688601 }}</ref>  Based on computer modeling, ligand interactions with CB2 receptor residues S3.31 and F5.46 appears to determine differences between CB<sub>1</sub> and CB<sub>2</sub> receptor selectivity.<ref name="pmid16451064">{{cite journal | vauthors = Tuccinardi T, Ferrarini PL, Manera C, Ortore G, Saccomanni G, Martinelli A | title = Cannabinoid CB2/CB1 selectivity. Receptor modeling and automated docking analysis | journal = Journal of Medicinal Chemistry | volume = 49 | issue = 3 | pages = 984–994 | date = February 2006 | pmid = 16451064 | doi = 10.1021/jm050875u }}</ref>  In CB<sub>2</sub> receptors, [[lipophilic]] groups interact with the F5.46 residue, allowing them to form a [[hydrogen bond]] with the S3.31 residue.<ref name="pmid16451064" /> 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.<ref name="pmid16451064" />
== Mechanism ==
Like the CB1 receptors, CB2 receptors inhibit the activity of [[adenylyl cyclase]] through their Gi/Go<sub>α</sub> subunits.<ref name="PMID16081674">{{cite journal | vauthors = Shoemaker JL, Ruckle MB, Mayeux PR, Prather PL | title = Agonist-directed trafficking of response by endocannabinoids acting at CB2 receptors | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 315 | issue = 2 | pages = 828–838 | date = November 2005 | pmid = 16081674 | doi = 10.1124/jpet.105.089474 | s2cid = 2759320 }}</ref><ref name="pmid16109430">{{cite journal | vauthors = Demuth DG, Molleman A | title = Cannabinoid signalling | journal = Life Sciences | volume = 78 | issue = 6 | pages = 549–563 | date = January 2006 | pmid = 16109430 | doi = 10.1016/j.lfs.2005.05.055 }}</ref> CB2 can also couple to stimulatory Gα<sub>s</sub> subunits leading to an increase of intracellular cAMP, as has been shown for human leukocytes.<ref name=":2">{{cite journal | vauthors = Saroz Y, Kho DT, Glass M, Graham ES, Grimsey NL | title = Cannabinoid Receptor 2 (CB<sub>2</sub>) Signals via G-alpha-s and Induces IL-6 and IL-10 Cytokine Secretion in Human Primary Leukocytes | journal = ACS Pharmacology & Translational Science | volume = 2 | issue = 6 | pages = 414–428 | date = December 2019 | pmid = 32259074 | pmc = 7088898 | doi = 10.1021/acsptsci.9b00049 | doi-access = free }}</ref> Through their G<sub>βγ</sub> subunits, CB2 receptors are also known to be coupled to the [[MAPK-ERK pathway]],<ref name="PMID16081674"/><ref name="pmid16109430" /><ref name="pmid8647116">{{cite journal | vauthors = Bouaboula M, Poinot-Chazel C, Marchand J, Canat X, Bourrié B, Rinaldi-Carmona M, Calandra B, Le Fur G, Casellas P | display-authors = 6 | title = Signaling pathway associated with stimulation of CB2 peripheral cannabinoid receptor. Involvement of both mitogen-activated protein kinase and induction of Krox-24 expression | journal = European Journal of Biochemistry | volume = 237 | issue = 3 | pages = 704–711 | date = May 1996 | pmid = 8647116 | doi = 10.1111/j.1432-1033.1996.0704p.x | doi-access =  }}</ref> a complex and highly conserved [[signal transduction]] pathway, which regulates a number of cellular processes in mature and developing tissues.<ref name= "pmid19182542">{{cite journal | vauthors = Shvartsman SY, Coppey M, Berezhkovskii AM | title = MAPK signaling in equations and embryos | journal = Fly | volume = 3 | issue = 1 | pages = 62–67 | year = 2009 | pmid = 19182542 | pmc = 2712890 | doi = 10.4161/fly.3.1.7776 }}</ref>  Activation of the MAPK-ERK pathway by CB2 receptor [[agonists]] acting through the G<sub>βγ</sub> subunit ultimately results in changes in [[cell migration]].<ref name="pmid9128257 ">{{cite journal | vauthors = Klemke RL, Cai S, Giannini AL, Gallagher PJ, de Lanerolle P, Cheresh DA | title = Regulation of cell motility by mitogen-activated protein kinase | journal = The Journal of Cell Biology | volume = 137 | issue = 2 | pages = 481–492 | date = April 1997 | pmid = 9128257 | pmc = 2139771 | doi = 10.1083/jcb.137.2.481 }}</ref>
Five recognized [[cannabinoids]] are produced endogenously: [[arachidonoylethanolamine]] (anandamide), [[2-arachidonoyl glycerol]] (2-AG), [[2-arachidonyl glyceryl ether]] (noladin ether), [[virodhamine]],<ref name="PMID16081674"/> as well as [[N-arachidonoyl-dopamine]] (NADA).<ref name="pmid11042139">{{cite journal | vauthors = Bisogno T, Melck D, Gretskaya NM, Bezuglov VV, De Petrocellis L, Di Marzo V | title = N-acyl-dopamines: novel synthetic CB(1) cannabinoid-receptor ligands and inhibitors of anandamide inactivation with cannabimimetic activity in vitro and in vivo | journal = The Biochemical Journal | volume = 351 Pt 3 | issue = Pt 3 | pages = 817–824 | date = November 2000 | pmid = 11042139 | pmc = 1221424 | doi = 10.1042/bj3510817 }}</ref>  Many of these ligands appear to exhibit properties of [[functional selectivity]] at the CB2 receptor:  2-AG activates the MAPK-ERK pathway, while noladin inhibits adenylyl cyclase.<ref name="PMID16081674"/>
== Expression ==
=== Dispute ===
Originally it was thought that the CB2 receptor was only expressed in peripheral tissue while the CB1 receptor is the endogenous receptor on neurons. Recent work with [[Immunohistochemistry|immunohistochemical staining]] has shown expression within neurons. Subsequently, it was shown that CB2 knock out mice produced the same [[Immunohistochemistry|immunohistochemical staining]], indicating the presence of the CB2 receptor where none was expressed. This has created a long history of debate as to whether the CB2 receptor is expressed in the CNS. A new mouse model was described in 2014 that expresses a fluorescent protein whenever CB2 is expressed within a cell. This has the potential to resolve questions about the expression of CB2 receptors in various tissues.<ref>{{cite journal | vauthors = Rogers N | title = Cannabinoid receptor with an 'identity crisis' gets a second look | journal = Nature Medicine | volume = 21 | issue = 9 | pages = 966–967 | date = September 2015 | pmid = 26340113 | doi = 10.1038/nm0915-966 | s2cid = 205382482 }}</ref>
=== Immune system ===
Initial investigation of CB2 receptor expression patterns focused on the presence of CB2 receptors in the peripheral tissues of the [[immune system]],<ref name="pmid7556170"/> and found the CB<sub>2</sub> receptor [[mRNA]] in the [[spleen]], [[tonsils]], and [[thymus gland]].<ref name="pmid7556170" /> CB<sub>2</sub> expression in human peripheral blood mononuclear cells at protein level has been confirmed by whole cell radioligand binding.<ref name=":2" /> [[Northern blot]] analysis further indicates the expression of the CNR2 gene in immune tissues,<ref name="pmid7556170" /> where they are primarily responsible for mediating [[cytokine]] release.<ref name="pmid16570099">{{cite journal | vauthors = Pertwee RG | title = The pharmacology of cannabinoid receptors and their ligands: an overview | journal = International Journal of Obesity | volume = 30 | pages = S13–S18 | date = April 2006 | issue = Suppl 1 | pmid = 16570099 | doi = 10.1038/sj.ijo.0803272 | s2cid = 13515221 | doi-access =  }}</ref> These receptors were localized on immune cells such as [[monocyte]]s, [[macrophages]],  [[B-cells]], and [[T-cells]].<ref name="pmid22048769"/><ref name="pmid7556170" />
=== Brain ===
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 CB<sub>1</sub> receptor and located on different cells.<ref name="pmid17356307">{{cite journal | vauthors = Onaivi ES | title = Neuropsychobiological evidence for the functional presence and expression of cannabinoid CB2 receptors in the brain | journal = Neuropsychobiology | volume = 54 | issue = 4 | pages = 231–246 | year = 2006 | pmid = 17356307 | doi = 10.1159/000100778 | doi-access = free }}</ref> Unlike the CB1 receptor, in the brain, CB2 receptors are found primarily on [[microglia]].<ref name="pmid16570099"/><ref name="pmid18037916">{{cite journal | vauthors = Cabral GA, Raborn ES, Griffin L, Dennis J, Marciano-Cabral F | title = CB2 receptors in the brain: role in central immune function | journal = British Journal of Pharmacology | volume = 153 | issue = 2 | pages = 240–251 | date = January 2008 | pmid = 18037916 | pmc = 2219530 | doi = 10.1038/sj.bjp.0707584 }}</ref> The CB2 receptor is expressed in some neurons within the [[central nervous system]] (e.g.; the [[brainstem]]), but the expression is very low.<ref>{{cite journal | vauthors = Van Sickle MD, Duncan M, Kingsley PJ, Mouihate A, Urbani P, Mackie K, Stella N, Makriyannis A, Piomelli D, Davison JS, Marnett LJ, Di Marzo V, Pittman QJ, Patel KD, Sharkey KA | display-authors = 6 | title = Identification and functional characterization of brainstem cannabinoid CB2 receptors | journal = Science | volume = 310 | issue = 5746 | pages = 329–332 | date = October 2005 | pmid = 16224028 | doi = 10.1126/science.1115740 | s2cid = 33075917 | bibcode = 2005Sci...310..329V | url = https://escholarship.org/uc/item/88q0m818 | authorlink8 = Alexandros Makriyannis }}</ref><ref>{{cite journal | vauthors = Gong JP, Onaivi ES, Ishiguro H, Liu QR, Tagliaferro PA, Brusco A, Uhl GR | title = Cannabinoid CB2 receptors: immunohistochemical localization in rat brain | journal = Brain Research | volume = 1071 | issue = 1 | pages = 10–23 | date = February 2006 | pmid = 16472786 | doi = 10.1016/j.brainres.2005.11.035 | s2cid = 25442161 }}</ref> CB2s are expressed on some rat retinal cell types.<ref name="pmid20803619">{{cite journal | vauthors = López EM, Tagliaferro P, Onaivi ES, López-Costa JJ | title = Distribution of CB2 cannabinoid receptor in adult rat retina | journal = Synapse | volume = 65 | issue = 5 | pages = 388–392 | date = May 2011 | pmid = 20803619 | doi = 10.1002/syn.20856 | s2cid = 206520909 }}</ref> Functional CB2 receptors are expressed in neurons of the ventral tegmental area and the hippocampus, arguing for a widespread expression and functional relevance in the CNS and in particular in neuronal signal transmission.<ref name="pmid26833913">{{cite journal | vauthors = Zhang HY, Gao M, Shen H, Bi GH, Yang HJ, Liu QR, Wu J, Gardner EL, Bonci A, Xi ZX | display-authors = 6 | title = Expression of functional cannabinoid CB<sub>2</sub> receptor in VTA dopamine neurons in rats | journal = Addiction Biology | volume = 22 | issue = 3 | pages = 752–765 | date = May 2017 | pmid = 26833913 | pmc = 4969232 | doi = 10.1111/adb.12367 }}</ref><ref name="pmid27133464">{{cite journal | vauthors = Stempel AV, Stumpf A, Zhang HY, Özdoğan T, Pannasch U, Theis AK, Otte DM, Wojtalla A, Rácz I, Ponomarenko A, Xi ZX, Zimmer A, Schmitz D | display-authors = 6 | title = Cannabinoid Type 2 Receptors Mediate a Cell Type-Specific Plasticity in the Hippocampus | journal = Neuron | volume = 90 | issue = 4 | pages = 795–809 | date = May 2016 | pmid = 27133464 | pmc = 5533103 | doi = 10.1016/j.neuron.2016.03.034 }}</ref>
=== Gastrointestinal system ===
CB2 receptors are also found throughout the [[gastrointestinal]] system, where they modulate intestinal inflammatory response.<ref name="pmid 15277313">{{cite journal | vauthors = Izzo AA | title = Cannabinoids and intestinal motility: welcome to CB2 receptors | journal = British Journal of Pharmacology | volume = 142 | issue = 8 | pages = 1201–1202 | date = August 2004 | pmid = 15277313 | pmc = 1575197 | doi = 10.1038/sj.bjp.0705890 }}</ref><ref name="pmid17906675">{{cite journal | vauthors = Wright KL, Duncan M, Sharkey KA | title = Cannabinoid CB2 receptors in the gastrointestinal tract: a regulatory system in states of inflammation | journal = British Journal of Pharmacology | volume = 153 | issue = 2 | pages = 263–270 | date = January 2008 | pmid = 17906675 | pmc = 2219529 | doi = 10.1038/sj.bjp.0707486 }}</ref>  Thus, CB2 receptor is a potential therapeutic target for [[inflammatory bowel diseases]], such as [[Crohn's disease]] and [[ulcerative colitis]].<ref name="pmid17906675" /><ref name="pmid 18469842">{{cite journal | vauthors = Capasso R, Borrelli F, Aviello G, Romano B, Scalisi C, Capasso F, Izzo AA | title = Cannabidiol, extracted from Cannabis sativa, selectively inhibits inflammatory hypermotility in mice | journal = British Journal of Pharmacology | volume = 154 | issue = 5 | pages = 1001–1008 | date = July 2008 | pmid = 18469842 | pmc = 2451037 | doi = 10.1038/bjp.2008.177 }}</ref> 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.  CB<sub>2</sub> activation may also have a role in the treatment of [[irritable bowel syndrome]].<ref>{{cite journal | vauthors = Storr MA, Yüce B, Andrews CN, Sharkey KA | title = The role of the endocannabinoid system in the pathophysiology and treatment of irritable bowel syndrome | journal = Neurogastroenterology and Motility | volume = 20 | issue = 8 | pages = 857–868 | date = August 2008 | pmid = 18710476 | doi = 10.1111/j.1365-2982.2008.01175.x | s2cid = 7045854 }}</ref> Cannabinoid receptor agonists reduce gut motility in IBS patients.<ref>{{cite journal | vauthors = Wong BS, Camilleri M, Busciglio I, Carlson P, Szarka LA, Burton D, Zinsmeister AR | title = Pharmacogenetic trial of a cannabinoid agonist shows reduced fasting colonic motility in patients with nonconstipated irritable bowel syndrome | journal = Gastroenterology | volume = 141 | issue = 5 | pages = 1638–47.e1–7 | date = November 2011 | pmid = 21803011 | pmc = 3202649 | doi = 10.1053/j.gastro.2011.07.036 }}</ref>
=== Peripheral nervous system ===
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 cell]]s, known to facilitate the inflammatory response. Cannabinoid mediated inhibition of these responses may cause a decrease in the perception of noxious-stimuli.<ref name="pmid11316486"/>
== Function ==
=== Immune system ===
Primary research on the functioning of the CB2 receptor has focused on the receptor's effects on the immunological activity of [[leukocytes]].<ref name="pmid10022233">{{cite journal | vauthors = Kaminski NE | title = Inhibition of the cAMP signaling cascade via cannabinoid receptors: a putative mechanism of immune modulation by cannabinoid compounds | journal = Toxicology Letters | volume = 102-103 | pages = 59–63 | date = December 1998 | pmid = 10022233 | doi = 10.1016/S0378-4274(98)00284-7 }}</ref> 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.<ref name="pmid22048769"/> Through their inhibition of adenylyl cyclase via their Gi/Go<sub>α</sub> subunits, CB2 receptor agonists cause a reduction in the intracellular levels of [[cyclic adenosine monophosphate]] (cAMP).<ref name="pmid9605425">{{cite journal | vauthors = Herring AC, Koh WS, Kaminski NE | title = Inhibition of the cyclic AMP signaling cascade and nuclear factor binding to CRE and kappaB elements by cannabinol, a minimally CNS-active cannabinoid | journal = Biochemical Pharmacology | volume = 55 | issue = 7 | pages = 1013–1023 | date = April 1998 | pmid = 9605425 | doi = 10.1016/S0006-2952(97)00630-8 }}</ref><ref name="pmid8937419">{{cite journal | vauthors = Kaminski NE | title = Immune regulation by cannabinoid compounds through the inhibition of the cyclic AMP signaling cascade and altered gene expression | journal = Biochemical Pharmacology | volume = 52 | issue = 8 | pages = 1133–1140 | date = October 1996 | pmid = 8937419 | doi = 10.1016/0006-2952(96)00480-7 }}</ref> CB2 also signals via Gα<sub>s</sub> and increases intracellular cAMP in human leukocytes, leading to induction of interleukins 6 and 10.<ref name=":2" /> 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]].<ref name="pmid10022233" /> This reduction causes changes in the expression of critical immunoregulatory genes<ref name="pmid9605425" /> and ultimately suppression of immune function.<ref name="pmid8937419" />
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]].<ref name="pmid17594182">{{cite journal | vauthors = Cheng Y, Hitchcock SA | title = Targeting cannabinoid agonists for inflammatory and neuropathic pain | journal = Expert Opinion on Investigational Drugs | volume = 16 | issue = 7 | pages = 951–965 | date = July 2007 | pmid = 17594182 | doi = 10.1517/13543784.16.7.951 | s2cid = 11159623 }}</ref> 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 hepatocellular carcinoma tumor samples.<ref>{{cite journal | vauthors = Pertwee RG | title = The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin | journal = British Journal of Pharmacology | volume = 153 | issue = 2 | pages = 199–215 | date = January 2008 | pmid = 17828291 | pmc = 2219532 | doi = 10.1038/sj.bjp.0707442 }}</ref>
CB2 receptors have also been implicated in the regulation of homing and retention of [[marginal zone]] [[B cell]]s. 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 [[Cyclic adenosine monophosphate|cAMP]] concentration, leading to reduced transcription of genes regulated by [[CREB]], indirectly increasing TCR signaling and [[Interleukin 2|IL-2]] production.<ref name="pmid22048769"/> Together, these findings demonstrate that the endocannabinoid system may be exploited to enhance immunity to certain pathogens and autoimmune diseases.
=== Clinical applications ===
CB2 receptors may have possible therapeutic roles in the treatment of neurodegenerative disorders such as [[Alzheimer's disease]].<ref name=pmid14657172>{{cite journal | vauthors = Benito C, Núñez E, Tolón RM, Carrier EJ, Rábano A, Hillard CJ, Romero J | title = Cannabinoid CB2 receptors and fatty acid amide hydrolase are selectively overexpressed in neuritic plaque-associated glia in Alzheimer's disease brains | journal = The Journal of Neuroscience | volume = 23 | issue = 35 | pages = 11136–11141 | date = December 2003 | pmid = 14657172 | pmc = 6741043 | doi = 10.1523/JNEUROSCI.23-35-11136.2003 }}</ref><ref name="pmid18291574">{{cite journal | vauthors = Fernández-Ruiz J, Pazos MR, García-Arencibia M, Sagredo O, Ramos JA | title = Role of CB2 receptors in neuroprotective effects of cannabinoids | journal = Molecular and Cellular Endocrinology | volume = 286 | issue = 1-2 Suppl 1 | pages = S91–S96 | date = April 2008 | pmid = 18291574 | doi = 10.1016/j.mce.2008.01.001 | s2cid = 33400848 | url = https://hal.archives-ouvertes.fr/hal-00531980/file/PEER_stage2_10.1016%252Fj.mce.2008.01.001.pdf }}</ref> Specifically, the CB2 agonist JWH-015 was shown to induce macrophages to remove native [[beta-amyloid]] protein from frozen human tissues.<ref name="pmid19505450">{{cite journal | vauthors = Tolón RM, Núñez E, Pazos MR, Benito C, Castillo AI, Martínez-Orgado JA, Romero J | title = The activation of cannabinoid CB2 receptors stimulates in situ and in vitro beta-amyloid removal by human macrophages | journal = Brain Research | volume = 1283 | issue = 11 | pages = 148–154 | date = August 2009 | pmid = 19505450 | doi = 10.1016/j.brainres.2009.05.098 | s2cid = 195685038 }}</ref> In patients with Alzheimer's disease, beta-amyloid proteins form aggregates known as [[senile plaques]], which disrupt neural functioning.<ref name="pmid15184601">{{cite journal | vauthors = Tiraboschi P, Hansen LA, Thal LJ, Corey-Bloom J | title = The importance of neuritic plaques and tangles to the development and evolution of AD | journal = Neurology | volume = 62 | issue = 11 | pages = 1984–1989 | date = June 2004 | pmid = 15184601 | doi = 10.1212/01.WNL.0000129697.01779.0A | s2cid = 25017332 }}</ref>
Changes in endocannabinoid levels and/or CB2 receptor expressions have been reported in almost all diseases affecting humans,<ref name="pmid21295074">{{cite journal | vauthors = Pacher P, Mechoulam R | title = Is lipid signaling through cannabinoid 2 receptors part of a protective system? | journal = Progress in Lipid Research | volume = 50 | issue = 2 | pages = 193–211 | date = April 2011 | pmid = 21295074 | pmc = 3062638 | doi = 10.1016/j.plipres.2011.01.001 }}</ref> 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 <ref name="pmid21295074" />
=== Modulation of cocaine reward ===
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]].<ref>{{cite journal | vauthors = Xi ZX, Peng XQ, Li X, Song R, Zhang HY, Liu QR, Yang HJ, Bi GH, Li J, Gardner EL | display-authors = 6 | title = Brain cannabinoid CB₂ receptors modulate cocaine's actions in mice | journal = Nature Neuroscience | volume = 14 | issue = 9 | pages = 1160–1166 | date = July 2011 | pmid = 21785434 | pmc = 3164946 | doi = 10.1038/nn.2874 }}</ref>
== Ligands ==
Many selective ligands for the CB2 receptor are now available.<ref name="pmid18289088">{{cite journal | vauthors = Marriott KS, Huffman JW | title = Recent advances in the development of selective ligands for the cannabinoid CB(2) receptor | journal = Current Topics in Medicinal Chemistry | volume = 8 | issue = 3 | pages = 187–204 | year = 2008 | pmid = 18289088 | doi = 10.2174/156802608783498014 | url = http://www.bentham-direct.org/pages/content.php?CTMC/2008/00000008/00000003/0003R.SGM | access-date = 2018-11-19 | url-status = usurped | archive-url = https://archive.today/20130112141316/http://www.bentham-direct.org/pages/content.php?CTMC/2008/00000008/00000003/0003R.SGM | archive-date = 2013-01-12 }}</ref>
=== Agonists ===
* [[Minocycline]]<ref name="pmid23960212">{{cite journal | vauthors = Lopez-Rodriguez AB, Siopi E, Finn DP, Marchand-Leroux C, Garcia-Segura LM, Jafarian-Tehrani M, Viveros MP | title = CB1 and CB2 cannabinoid receptor antagonists prevent minocycline-induced neuroprotection following traumatic brain injury in mice | journal = Cerebral Cortex | volume = 25 | issue = 1 | pages = 35–45 | date = January 2015 | pmid = 23960212 | doi = 10.1093/cercor/bht202 | doi-access = free }}</ref>
=== Partial agonists ===
* [[GW-405,833]]
=== Unspecified efficacy agonists ===
* [[AM-1241]]
* [[HU-308]]
* [[JWH-015]]
* [[JWH-133]]
* [[L-759,633]]
* [[L-759,656]]
==== Herbal ====
* [[Echinacea purpurea]]<ref>{{cite journal | vauthors = Liu R, Caram-Salas NL, Li W, Wang L, Arnason JT, Harris CS | title = Interactions of ''Echinacea'' spp. Root Extracts and Alkylamides With the Endocannabinoid System and Peripheral Inflammatory Pain | journal = Frontiers in Pharmacology | volume = 12 | pages = 651292 | date = 2021-04-27 | pmid = 33986678 | pmc = 8111300 | doi = 10.3389/fphar.2021.651292 | doi-access = free }}</ref>
=== Inverse agonists ===
* [[AM-630]]
* [[BML-190]]
* [[JTE-907]]
* [[SR-144,528]]
* [[APD371]]
== Binding affinities ==
{| class="wikitable sortable" style="font-size: smaller; text-align: center; width: auto;"
|-
! style="width: 12em"|
! CB<sub>1</sub> affinity (K<sub>i</sub>)
! Efficacy towards CB<sub>1</sub>
! CB<sub>2</sub> affinity (K<sub>i</sub>)
! Efficacy towards CB<sub>2</sub>
! Type
! References
|-
! '''[[Anandamide]]'''
| 78 nM
| Partial agonist
| 370 nM
| Partial agonist
| Endogenous
|
|-
! [[N-Arachidonoyl dopamine]]
| 250 nM
| Agonist
| 12000 nM
| ?
| Endogenous
|<ref name="2AG">{{cite journal | vauthors = Pertwee RG, Howlett AC, Abood ME, Alexander SP, Di Marzo V, Elphick MR, Greasley PJ, Hansen HS, Kunos G, Mackie K, Mechoulam R, Ross RA | display-authors = 6 | title = International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB₁ and CB₂ | journal = Pharmacological Reviews | volume = 62 | issue = 4 | pages = 588–631 | date = December 2010 | pmid = 21079038 | pmc = 2993256 | doi = 10.1124/pr.110.003004 }}</ref>
|-
! [[2-Arachidonoylglycerol]]
| 58.3 nM
| Full agonist
| 145 nM
| Full agonist
| Endogenous
|<ref name="2AG"/>
|-
! [[2-Arachidonyl glyceryl ether]]
| 21 nM
| Full agonist
| 480 nM
| Full agonist
| Endogenous
|
|-
!  '''[[Tetrahydrocannabinol]]'''
|  10 nM
|  Partial agonist
|  24 nM
|  Partial agonist
|  Phytogenic
| <ref name="whoa">{{cite web|title=PDSP Database - UNC|url=http://pdsp.med.unc.edu/pdsp.php?|access-date=11 June 2013|url-status=dead|archive-url=https://web.archive.org/web/20131108013656/http://pdsp.med.unc.edu/pdsp.php|archive-date=8 November 2013}}</ref>
|-
! [[EGCG]]
| 33.6 μM
| Agonist
| >50 μM
| ?
| Phytogenic
|<ref name=":0">{{cite journal | vauthors = Korte G, Dreiseitel A, Schreier P, Oehme A, Locher S, Geiger S, Heilmann J, Sand PG | display-authors = 6 | title = Tea catechins' affinity for human cannabinoid receptors | journal = Phytomedicine | volume = 17 | issue = 1 | pages = 19–22 | date = January 2010 | pmid = 19897346 | doi = 10.1016/j.phymed.2009.10.001 }}</ref>
|-
![[Epigallocatechin gallate|EGC]]
|35.7 μM
|Agonist
|>50 μM
|?
|Phytogenic
|<ref name=":0" />
|-
![[Epicatechin gallate|ECG]]
|47.3 μM
|Agonist
|>50 μM
|?
|Phytogenic
|<ref name=":0" />
|-
!''N''-alkylamide
| -
| -
|<100 nM
|Partial agonist
|Phytogenic
|<ref name=":1">{{cite journal | vauthors = Gertsch J, Pertwee RG, Di Marzo V | title = Phytocannabinoids beyond the Cannabis plant - do they exist? | journal = British Journal of Pharmacology | volume = 160 | issue = 3 | pages = 523–529 | date = June 2010 | pmid = 20590562 | pmc = 2931553 | doi = 10.1111/j.1476-5381.2010.00745.x }}</ref>
|-
!'''β-'''[[Caryophyllene]]
| -
| -
|<200 nM
|Full agonist
|Phytogenic
|<ref name=":1" />
|-
![[Falcarinol]]
|<1 μM
|Inverse agonist
|?
|?
|Phytogenic
|<ref name=":1" />
|-
![[Rutamarin]]
| -
| -
|<10 μM
|?
|Phytogenic
|<ref name=":1" />
|-
![[3,3'-Diindolylmethane]]
| -
| -
|1 μM
|Partial Agonist
|Phytogenic
|<ref name=":1" />
|-
!  [[AM-1221]]
|  52.3 nM
|  Agonist
|  0.28 nM
|  Agonist
|  Synthetic
| <ref name="dude">{{Ref patent2 |country= WO |number= 200128557 |status= granted |title= Cannabimimetic indole derivatives |pubdate= 2001-04-26 |gdate= 2001-06-07 |pridate= 1999-10-18 |inventor= Makriyannis A, Deng H }}</ref>
|-
!  [[AM-1235]]
|  1.5 nM
|  Agonist
|  20.4 nM
|  Agonist
|  Synthetic
| <ref name="like">{{Ref patent2 | country = US | number = 7241799 | status = granted | title = Cannabimimetic indole derivatives | pubdate = 2004-11-05 | gdate = 2007-07-10 | pridate= 2004-11-05 | inventor = Makriyannis A, Deng H | assign1= }}</ref>
|-
!  [[AM-2232]]
|  0.28 nM
|  Agonist
|  1.48 nM
|  Agonist
|  Synthetic
|  <ref name="like"/>
|-
!  [[UR-144]]
|  150 nM
|  Full agonist
|  1.8 nM
|  Full agonist
|  Synthetic
| <ref name="myhandsareamazing">{{cite journal | vauthors = Frost JM, Dart MJ, Tietje KR, Garrison TR, Grayson GK, Daza AV, El-Kouhen OF, Yao BB, Hsieh GC, Pai M, Zhu CZ, Chandran P, Meyer MD | display-authors = 6 | title = Indol-3-ylcycloalkyl ketones: effects of N1 substituted indole side chain variations on CB(2) cannabinoid receptor activity | journal = Journal of Medicinal Chemistry | volume = 53 | issue = 1 | pages = 295–315 | date = January 2010 | pmid = 19921781 | doi = 10.1021/jm901214q }}</ref>
|-
!  [[JWH-007]]
|  9.0 nM
|  Agonist
|  2.94 nM
|  Agonist
|  Synthetic
|  <ref name="pass">{{cite journal | vauthors = Aung MM, Griffin G, Huffman JW, Wu M, Keel C, Yang B, Showalter VM, Abood ME, Martin BR | display-authors = 6 | title = Influence of the N-1 alkyl chain length of cannabimimetic indoles upon CB(1) and CB(2) receptor binding | journal = Drug and Alcohol Dependence | volume = 60 | issue = 2 | pages = 133–140 | date = August 2000 | pmid = 10940540 | doi = 10.1016/S0376-8716(99)00152-0 }}</ref>
|-
!  [[JWH-015]]
|  383 nM
|  Agonist
|  13.8 nM
|  Agonist
|  Synthetic
| <ref name="pass"/>
|-
!  [[JWH-018]]
|  9.00 ± 5.00 nM
|  Full agonist
|  2.94 ± 2.65 nM
|  Full agonist
|  Synthetic
| <ref name="pass"/>
|-
|}
== Evolution ==
=== [[Sequence homology|Paralogues]] ===
Source:<ref>{{Cite web |title=GeneCards®: The Human Gene Database |url=https://www.genecards.org/cgi-bin/carddisp.pl?gene=CNR2&keywords=cnr2#paralogs}}</ref>
* [[Cannabinoid receptor 1|CNR1]]
* [[GPR12]]
* [[GPR6]]
* [[S1PR1]]
* [[S1PR4]]
* [[S1PR3]]
* [[S1PR5]]
* [[S1PR2]]
* [[LPAR1]]
* [[GPR3]]
* [[LPAR3]]
* [[LPAR2]]
* [[Melanocortin 4 receptor|MC4R]]
* [[Melanocortin 5 receptor|MC5R]]
* [[GPR119]]
* [[Melanocortin 1 receptor|MC1R]]
* [[Melanocortin 3 receptor|MC3R]]
* [[ACTH receptor|MC2R]]
== References ==
{{Reflist|33em}}
== External links ==
* {{cite web | url = http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2207 | title = Cannabinoid Receptors: CB<sub>2</sub> | work = IUPHAR Database of Receptors and Ion Channels | publisher = International Union of Basic and Clinical Pharmacology | access-date = 2008-11-25 | archive-url = https://web.archive.org/web/20120305214640/http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2207 | archive-date = 2012-03-05 | url-status = dead }}
* [https://www.proteinatlas.org/ENSG00000188822-CNR2 Cannabinoid Receptor 2 (CNR2) Human Protein Atlas]
{{NLM content}}
{{G protein-coupled receptors}}
{{Cannabinoidergics}}
{{DEFAULTSORT:Cannabinoid Receptor 2 (Macrophage)}}
[[Category:G protein-coupled receptors]]