Cannabinoid receptor

Cannabinoid receptor

Name=cannabinoid receptor 1 (brain)

Name=cannabinoid receptor 2 (macrophage)

The cannabinoid receptors are a class of receptors under the G-protein coupled receptor superfamily. Their ligands are known as cannabinoids or endocannabinoids depending on whether they come from external or internal (endogenous) sources, respectively.


There are currently two known subtypes, CB1cite journal | author = Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI | title = Structure of a cannabinoid receptor and functional expression of the cloned cDNA | journal = Nature | volume = 346 | issue = 6284 | pages = 561–4 | year = 1990 | pmid = 2165569 | doi = 10.1038/346561a0 ] cite journal | author = Gérard CM, Mollereau C, Vassart G, Parmentier M | title = Molecular cloning of a human cannabinoid receptor which is also expressed in testis | journal = Biochem. J. | volume = 279 ( Pt 1) | issue = | pages = 129–34 | year = 1991 | pmid = 1718258 | doi = | issn = | url =] which is expressed mainly in the brain, but also in the lungs, liver and kidneys and CB2 which is mainly expressed in the immune system and in hematopoietic cells. Mounting evidence suggests that there are novel cannabinoid receptorscite journal | author = Begg M, Pacher P, Bátkai S, Osei-Hyiaman D, Offertáler L, Mo FM, Liu J, Kunos G | title = Evidence for novel cannabinoid receptors | journal = Pharmacol. Ther. | volume = 106 | issue = 2 | pages = 133–45 | year = 2005 | pmid = 15866316 | doi = 10.1016/j.pharmthera.2004.11.005 ] that is, non-CB1 and non-CB2, which are expressed in endothelial cells and in the CNS. In 2007, the binding of several cannabinoids to a GPCR in the brain was described.cite journal | author = Ryberg E, Larsson N, Sjögren S, Hjorth S, Hermansson NO, Leonova J, Elebring T, Nilsson K, Drmota T, Greasley PJ | title = The orphan receptor GPR55 is a novel cannabinoid receptor | journal = Br. J. Pharmacol. | volume = 152 | issue = 7 | pages = 1092–101 | year = 2007 | pmid = 17876302 | doi = 10.1038/sj.bjp.0707460 ]

The protein sequences of CB1 and CB2 receptors are about 44% similar.cite journal | author = 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 | year = 1993 | pmid = 7689702 ] In addition, minor variations in each receptor have been identified. Cannabinoids bind reversibly and stereo-selectively to the cannabinoid receptors. The affinity of an individual cannabinoid to each receptor determines the effect of that cannabinoid. Cannabinoids that bind more selectively to certain receptors are more desirable for medical usage.


Cannabinoid receptor type 1 (CB1) receptors are thought to be the most widely expressed G-protein coupled receptors in the brain. This is due to endocannabinoid-mediated depolarization-induced suppression of inhibition, a very common form of short-term plasticity in which the depolarization of a single neuron induces a reduction in GABA-mediated neurotransmission. Endocannabinoids released from the depolarized neuron bind to CB1 receptors in the pre-synaptic neuron and cause a reduction in GABA release.

They are also found in other parts of the body. For instance, in the liver, activation of the CB1 receptor is known to increase de novo lipogenesis,cite journal | author = Osei-Hyiaman D, DePetrillo M, Pacher P, Liu J, Radaeva S, Bátkai S, Harvey-White J, Mackie K, Offertáler L, Wang L, Kunos G | title = Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity | journal = J. Clin. Invest. | volume = 115 | issue = 5 | pages = 1298–305 | year = 2005 | pmid = 15864349 | doi = 10.1172/JCI200523057 ] Activation of presynaptic CB1 receptors is also known to inhibit sympathetic innervation of blood vessels and contributes to the suppression of the neurogenic vasopressor response in septic shock.cite journal | author = Godlewski G, Malinowska B, Schlicker E | title = Presynaptic cannabinoid CB1 receptors are involved in the inhibition of the neurogenic vasopressor response during septic shock in pithed rats | journal = Br. J. Pharmacol. | volume = 142 | issue = 4 | pages = 701–8 | year = 2004 | pmid = 15159284 | doi = 10.1038/sj.bjp.0705839 ]


CB2 receptors are mainly expressed on T cells of the immune system, on macrophages and B cells, and in hematopoietic cells. They also have a function in keratinocytes, and are expressed on mouse pre-implantation embryos. It is also expressed on peripheral nerve terminals.In the brain, they are mainly expressed by microglial cells, where their role remains unclear.

Other cannabinoid receptors

The existance of additional cannabinoid receptors has long been suspected, due to the actions of compounds such as abnormal cannabidiol which produce cannabinoid-like effects on blood pressure and inflammation, yet do not activate either CB1 or CB2. [Járai Z, Wagner JA, Varga K, Lake KD, Compton DR, Martin BR, Zimmer AM, Bonner TI, Buckley NE, Mezey E, Razdan RK, Zimmer A, Kunos G. Cannabinoid-induced mesenteric vasodilation through an endothelial site distinct from CB1 or CB2 receptors. "Proceedings of the National Academy of Sciences USA". 1999 Nov 23;96(24):14136-41. PMID 10570211] [Ho WS, Hiley CR. Vasodilator actions of abnormal-cannabidiol in rat isolated small mesenteric artery. "British Journal of Pharmacology". 2003 Apr;138(7):1320-32. PMID 12711633] [McHugh D, Tanner C, Mechoulam R, Pertwee RG, Ross RA. Inhibition of human neutrophil chemotaxis by endogenous cannabinoids and phytocannabinoids: evidence for a site distinct from CB1 and CB2. "Molecular Pharmacology". 2008 Feb;73(2):441-50. PMID 17965195] Recent molecular biology research suggested that the orphan receptor GPR55 should in fact be characterised as a cannabinoid receptor, on the basis of sequence homology at the binding site. Subsequent studies showed that GPR55 does indeed respond to cannabinoid ligands. [Johns DG, Behm DJ, Walker DJ, Ao Z, Shapland EM, Daniels DA, Riddick M, Dowell S, Staton PC, Green P, Shabon U, Bao W, Aiyar N, Yue TL, Brown AJ, Morrison AD, Douglas SA. The novel endocannabinoid receptor GPR55 is activated by atypical cannabinoids but does not mediate their vasodilator effects. "British Journal of Pharmacology". 2007 Nov;152(5):825-31. PMID 17704827] [Ryberg E, Larsson N, Sjögren S, Hjorth S, Hermansson NO, Leonova J, Elebring T, Nilsson K, Drmota T, Greasley PJ. The orphan receptor GPR55 is a novel cannabinoid receptor. "British Journal of Pharmacology". 2007 Dec;152(7):1092-101. PMID 17876302] This profile as a distinct non-CB1/CB2 receptor which responds to a variety of both endogenous and exogenous cannabinoid ligands, has led some groups to suggest GPR55 should be categorised as the CB3 receptor, and this re-classification may follow in time. [Overton H, Babbs A, Doel S, Fyfe M, Gardner L, Griffin G, Jackson H, Procter M, Rasamison C, Tang-Christensen M. Deorphanization of a G protein-coupled receptor for oleoylethanolamide and its use in the discovery of small-molecule hypophagic agents. "Cell Metabolism" 2003; 3(3):167-175.] However this is complicated by the fact that another possible cannabinoid receptor has been discovered in the hippocampus, although its gene has not yet been cloned, [ [ De Fonseca FR, Schneider M. The endogenous cannabinoid system and drug addiction: 20 years after the discovery of the CB1 receptor. "Addiction Biology" 2008; 13:143-146.] ] suggesting that there may be at least two more cannabinoid receptors to be discovered, in addition to the two that are already known.


Cannabinoid receptors are activated by cannabinoids, generated naturally inside the body (endocannabinoids) or introduced into the body as cannabis or a related synthetic compound.

After the receptor is engaged, multiple intracellular signal transduction pathways are activated. At first, it was thought that cannabinoid receptors mainly inhibited the enzyme adenylate cyclase (and thereby the production of the second messenger molecule cyclic AMP), and positively influenced inwardly rectifying potassium channels (=Kir or IRK).cite journal | author = Demuth DG, Molleman A | title = Cannabinoid signalling | journal = Life Sci. | volume = 78 | issue = 6 | pages = 549–63 | year = 2006 | pmid = 16109430 | doi = 10.1016/j.lfs.2005.05.055 ] However, a much more complex picture has appeared in different cell types, implicating other potassium ion channels, calcium channels, protein kinase A and C, Raf-1, ERK, JNK, p38, c-fos, c-jun and many more.

Separation between the therapeutically undesirable psychotropic effects, and the clinically desirable ones however, has not been reported with agonists that bind to cannabinoid receptors. THC, as well as the two major endogenous compounds identified so far that bind to the cannabinoid receptors —anandamide and 2-arachidonylglycerol (2-AG)— produce most of their effects by binding to both the CB1 and CB2 cannabinoid receptors. While the effects mediated by CB1, mostly in the CNS, have been thoroughly investigated, those mediated by CB2 are not equally well defined.


Gastrointestinal activity

Inhibition of gastrointestinal activity has been observed after administration of Δ9-THC, or of anandamide. This effect has been assumed to be CB1-mediated since the specific CB1 antagonist SR 141716A (Rimonabant) blocks the effect. Another report, however, suggests that inhibition of intestinal motility may also have a CB2-mediated component.cite journal | author = Mathison R, Ho W, Pittman QJ, Davison JS, Sharkey KA | title = Effects of cannabinoid receptor-2 activation on accelerated gastrointestinal transit in lipopolysaccharide-treated rats | journal = Br. J. Pharmacol. | volume = 142 | issue = 8 | pages = 1247–54 | year = 2004 | pmid = 15249429 | doi = 10.1038/sj.bjp.0705889 ]

Cardiovascular activity

Cannabinoids are well known for their cardiovascular activity. Activation of peripheral CB1 receptors contributes to hemorrhagic and endotoxin-induced hypotension. Anandamide and 2-AG, produced by macrophages and platelets respectively, may mediate this effect.

The hypotension in hemorrhaged rats was prevented by the CB1 antagonist SR 141716A. Recently the same group found that anandamide-induced mesenteric vasodilation is mediated by an endothelially located SR 141716A-sensitive "anandamide receptor," distinct from the CB1 cannabinoid receptor, and that activation of such a receptor by an endocannabinoid, possibly anandamide, contributes to endotoxin-induced mesenteric vasodilation "in vivo". The highly potent synthetic cannabinoid HU-210, as well as 2-AG, had no mesenteric vasodilator activity. Furthermore it was shown that mesenteric vasodilation by anandamide apparently has 2 components, one mediated by a SR 141716-sensitive non-CB1 receptor (located on the endothelium) and the other by an SR 141716A-resistant direct action on vascular smooth muscle.

The production of 2-AG is enhanced in normal, but not in endothelium-denuded rat aorta on stimulation with Carbachol, an acetylcholine receptor agonist. 2-AG potently reduces blood pressure in rats and may represent an endothelium-derived hypotensive factor.


Anandamide attenuates the early phase or the late phase of pain behavior produced by formalin-induced chemical damage. This effect is produced by interaction with CB1 (or CB1-like) receptors, located on peripheral endings of sensory neurons involved in pain transmission. Palmitylethanolamide, which like anandamide is present in the skin, also exhibits peripheral antinociceptive activity during the late phase of pain behavior. Palmitylethanolamide, however does not bind to either CB1 or CB2. Its analgetic activity is blocked by the specific CB2 antagonist SR 144528, though not by the specific CB1 antagonist SR 141716A. Hence a CB2-like receptor was postulated.

Cannabinoid treatments

Cannabis sativa preparations have been known as therapeutic agents against various diseases for millennia.cite journal | author = Pacher P, Bátkai S, Kunos G | title = The endocannabinoid system as an emerging target of pharmacotherapy | journal = Pharmacol. Rev. | volume = 58 | issue = 3 | pages = 389–462 | year = 2006 | pmid = 16968947 | doi = 10.1124/pr.58.3.2 ] The native active constituent, Δ9-tetrahydrocannabinol9-THC) was found to be the principal mediator of the effects of cannabis.cite journal | author = Gaoni Y, Mechoulam R | title = Isolation, structure and partial synthesis of an active constituent of hashish | journal = J. Am. Chem. Soc. | volume = 86 | issue = 8 | pages = 1646–1647 | year = 1964| doi = 10.1021/ja01062a046 ] Synthetic Δ9-THC is prescribed today under the generic name Dronabinol, to treat vomiting and for enhancement of appetite, mainly in AIDS patients.U.S. Pat. No. 5,434,295 discloses a family of novel 4-phenyl pinene derivatives, and teaches how to use those compounds in pharmaceutical compositions useful for treating various pathological conditions associated with damage to the central nervous system. U.S. Pat. No. 4,282,248 discloses additional pinene derivatives. These patents do not mention that any of the disclosed compounds are selective for peripheral cannabinoid receptors.

Several synthetic cannabinoids have been shown to bind to the CB2 receptor with a higher affinity than to the CB1 receptor. Most of these compounds exhibit only modest selectivity. One of the described compounds, a classical THC-type cannabinoid, L-759,656, in which the phenolic group is blocked as a methyl ether, has a CB1/CB2 binding ratio > 1000. The pharmacology of those known agonists has yet to be described.

Certain tumors, especially gliomas, express CB2 receptors. Guzman and coworkers have shown that Δ9-tetrahydrocannabinol and WIN-55,212-2, two non-selective cannabinoid agonists, induce the regression or eradication of malignant brain tumors in rats and mice.cite journal | author = Galve-Roperh I, Sánchez C, Cortés ML, del Pulgar TG, Izquierdo M, Guzmán M | title = Anti-tumoral action of cannabinoids: involvement of sustained ceramide accumulation and extracellular signal-regulated kinase activation | journal = Nat. Med. | volume = 6 | issue = 3 | pages = 313–9 | year = 2000 | pmid = 10700234 | doi = 10.1038/73171 ] CB2 selective agonists are effective in the treatment of pain, various inflammatory diseases in different animal models,cite journal | author = Whiteside GT, Lee GP, Valenzano KJ | title = The role of the cannabinoid CB2 receptor in pain transmission and therapeutic potential of small molecule CB2 receptor agonists | journal = Curr. Med. Chem. | volume = 14 | issue = 8 | pages = 917–36 | year = 2007 | pmid = 17430144| doi = 10.2174/092986707780363023 ] cite journal | author = 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 | title = Peripheral cannabinoid receptor, CB2, regulates bone mass | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 103 | issue = 3 | pages = 696–701 | year = 2006 | pmid = 16407142 | doi = 10.1073/pnas.0504187103 ] osteoporosiscite journal | author = 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 | title = Peripheral cannabinoid receptor, CB2, regulates bone mass | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 103 | issue = 3 | pages = 696–701 | year = 2006 | pmid = 16407142 | doi = 10.1073/pnas.0504187103 ] and atherosclerosis.cite journal | author = Steffens S, Veillard NR, Arnaud C, Pelli G, Burger F, Staub C, Karsak M, Zimmer A, Frossard JL, Mach F | title = Low dose oral cannabinoid therapy reduces progression of atherosclerosis in mice | journal = Nature | volume = 434 | issue = 7034 | pages = 782–6 | year = 2005 | pmid = 15815632 | doi = 10.1038/nature03389 ] CB1 selective antagonists are used for weight reduction and smoking cessation (see Rimonabant). Activation of CB1 provides neuroprotection after brain injury.cite journal | author = Panikashvili D, Simeonidou C, Ben-Shabat S, Hanus L, Breuer A, Mechoulam R, Shohami E | title = An endogenous cannabinoid (2-AG) is neuroprotective after brain injury | journal = Nature | volume = 413 | issue = 6855 | pages = 527–31 | year = 2001 | pmid = 11586361 | doi = 10.1038/35097089 ]


External links

* [ IUPHAR GPCR Database - Cannabinoid Receptors]

* [ The Endocannabinoid System Network (ECSN) - CB1 receptor]

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