Cannabinoid receptor

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File:Cb1 cb2 structure.png
CB1 and CB2 structures.
cannabinoid receptor 1 (brain)
220px
NMR solution structure of a peptide mimetic of the fourth cytoplasmic loop of the CB1 cannabinoid receptor based on the PDB 2b0y coordinates.
Identifiers
Symbol CNR1
Alt. symbols CNR
Entrez 1268
HUGO 2159
OMIM 114610
RefSeq NM_033181
UniProt P21554
Other data
Locus Chr. 6 q14-q15
cannabinoid receptor 2 (macrophage)
Identifiers
Symbol CNR2
Entrez 1269
HUGO 2160
OMIM 605051
RefSeq NM_001841
UniProt P34972
Other data
Locus Chr. 1 p

The cannabinoid receptors are a class of cell membrane receptors under the G protein-coupled receptor superfamily.[1][2][3] As is typical of G protein-coupled receptors, the cannabinoid receptors contain seven transmembrane spanning domains. [4] Cannabinoid receptors are activated by three major group of ligands, endocannabinoids (produced by the mammalian body), plant cannabinoids (such as THC, produced by the cannabis plant) and synthetic cannabinoids (such as HU-210). All of the endocannabinoids and plant cannabinoids are lipophilic, i.e. fat soluble, compounds.

There are currently two known subtypes, termed CB1 and CB2.[5][6] The CB1 receptor is expressed mainly in the brain (central nervous system, CNS), but also in the lungs, liver and kidneys. The CB2 receptor is mainly expressed in the immune system and in hematopoietic cells. Mounting evidence suggests that there are novel cannabinoid receptors[7] 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 G protein-coupled receptor (GPCR) in the brain was described.[8]

The protein sequences of CB1 and CB2 receptors are about 44% similar.[9] When only the transmembrane regions of the receptors are considered, amino acid similarity between the two receptor subtypes is approximately 68%. [4] 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.


CB1

Main article: Cannabinoid receptor type 1

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,[10] 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.[11]

A study done on CB1 knockout mice (genetically altered mice that cannot produce CB1) showed an increase in mortality rate. They also displayed suppressed locomotor activity as well as hypoalgesia (decreased pain sensitivity). The CB1 knockout mice did respond to Delta9-Tetrahydrocannabinol THC. This shows that either CB2 or unknown cannabinoid receptors also have pharmacologic significance[12] .

CB2

Main article: CB2 receptor

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. Current research suggests that these receptors play a role in nociception, or the perception of pain. In the brain, they are mainly expressed by microglial cells, where their role remains unclear.

Other cannabinoid receptors

The existence of additional cannabinoid receptors has long been suspected, due to the actions of compounds such as abnormal cannabidiol that produce cannabinoid-like effects on blood pressure and inflammation, yet do not activate either CB1 or CB2.[13][14][15] Recent research strongly supports the hypothesis that the N-arachidonoyl glycine (NAGly) receptor GPR18 is the molecular identity of the abnormal cannabidiol receptor and additionally suggests that NAGly, the endogenous lipid metabolite of AEA, initiates directed microglial migration in the CNS through activation of GPR18.[16]Other molecular biology studies have 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.[17][8] This profile as a distinct non-CB1/CB2 receptor that 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.[18] 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,[19] suggesting that there may be at least two more cannabinoid receptors to be discovered, in addition to the two that are already known. GPR119 has been suggested as a fifth possible cannabinoid receptor.[20]

Signaling

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).[21] 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.[21]

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 central nervous system, have been thoroughly investigated, those mediated by CB2 are not equally well defined.

Physiology

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.[22]

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.

Pain

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 (rimonabant). Hence a CB2-like receptor was postulated.

In experiments on mice, a chemical designated JZL184 that inhibits a naturally occurring enzyme MAGL from degrading a pain relieving endocannabinoid called 2-arachidonoylglycerol (AG) increases the brain concentration of AG and thereby induces analgesia.[23][24]

Bone

The endocannabinoid system through CB2 signaling plays a key role in the maintenance of bone mass. CB2 is expressed in osteoblasts, osteocytes, and osteoclasts. CB2 agonists enhance endocortical osteoblast number and activity while restraining trabecular osteoclastogenesis. Another important effect is that CB2 agonists attenuates ovariectomy-induced bone loss while increasing cortical thickness. These findings suggest CB2 offers a potential molecular target for the diagnosis and treatment of osteoporosis.[25]

Cannabinoid treatments

Main article: Medical cannabis

Cannabis sativa preparations have been known as therapeutic agents against various diseases for millennia.[26] The native active constituent, Δ9-tetrahydrocannabinol (Δ9-THC) was found to be the principal mediator of the effects of cannabis.[27] Synthetic Δ9-THC is prescribed today under the generic name Dronabinol, to treat vomiting and for enhancement of appetite, mainly in AIDS patients.

Several synthetic cannabinoids have been shown to bind to the CB2 receptor with a higher affinity than to the CB1 receptor.[28] 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.[29] The pharmacology of these 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.[30] CB2 selective agonists are effective in the treatment of pain, various inflammatory diseases in different animal models,[31][25] osteoporosis[25] and atherosclerosis.[32] CB1 selective antagonists are used for weight reduction and smoking cessation (see Rimonabant). Activation of CB1 provides neuroprotection after brain injury.[33]

Several studies have also concluded that certain cannabinoids might have the ability to prevent Alzheimer's disease.[34][35]

NMR Imaging

The protein image was created using nuclear magnetic resonance to determine 3-D structure. The picture represents the fourth cytoplasmic loop of the CB1 cannabinoid receptor.

See also

References

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External links

Class A: Rhodopsin like
α1 (A, B, D) · α2 (A, B, C) · β1 · β2 · β3
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Class C: Metabotropic
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de:Endocannabinoid-System

it:Recettori cannabinoidi pl:Receptory kannabinoidowe pt:Receptor canabinoide ru:Каннабиноидные рецепторы

fi:Kannabinoidireseptori
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  8. ↑ 8.0 8.1 Ryberg E, Larsson N, Sjögren S, Hjorth S, Hermansson NO, Leonova J, Elebring T, Nilsson K, Drmota T, Greasley PJ (2007). "The orphan receptor GPR55 is a novel cannabinoid receptor". Br. J. Pharmacol. 152 (7): 1092–101. doi:10.1038/sj.bjp.0707460. PMC 2095107 Freely accessible. PMID 17876302. 
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  22. ↑ Mathison R, Ho W, Pittman QJ, Davison JS, Sharkey KA (2004). "Effects of cannabinoid receptor-2 activation on accelerated gastrointestinal transit in lipopolysaccharide-treated rats". Br. J. Pharmacol. 142 (8): 1247–54. doi:10.1038/sj.bjp.0705889. PMC 1575196 Freely accessible. PMID 15249429. 
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  26. ↑ Pacher P, Bátkai S, Kunos G (2006). "The endocannabinoid system as an emerging target of pharmacotherapy". Pharmacol. Rev. 58 (3): 389–462. doi:10.1124/pr.58.3.2. PMC 2241751 Freely accessible. PMID 16968947. 
  27. ↑ Gaoni Y, Mechoulam R (1964). "Isolation, structure and partial synthesis of an active constituent of hashish". J. Am. Chem. Soc. 86 (8): 1646–1647. doi:10.1021/ja01062a046. 
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  32. ↑ Steffens S, Veillard NR, Arnaud C, Pelli G, Burger F, Staub C, Karsak M, Zimmer A, Frossard JL, Mach F (2005). "Low dose oral cannabinoid therapy reduces progression of atherosclerosis in mice". Nature. 434 (7034): 782–6. doi:10.1038/nature03389. PMID 15815632. 
  33. ↑ Panikashvili D, Simeonidou C, Ben-Shabat S, Hanuš L, Breuer A, Mechoulam R, Shohami E (2001). "An endogenous cannabinoid (2-AG) is neuroprotective after brain injury". Nature. 413 (6855): 527–31. doi:10.1038/35097089. PMID 11586361. 
  34. ↑ Ramíirez, B. G., C. Blázquez, T. Gómez del Pulgar, M. Guzmán, and M. L. de Ceballos (2005). "Prevention of Alzheimer's disease pathology by cannabinoids: neuroprotection mediated by blockade of microglial activation". Journal of Neuroscience. 25 (8^): 1904–1913. doi:10.1523/JNEUROSCI.4540-04.2005. PMID 15728830. Retrieved 2007-02-27. 
  35. ↑ Webber, Stephanie (2009-01-27). "Marijuana could prevent Alzheimer's". The Lantern. Archived from the original on January 27, 2009. 
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