Cannabinoid receptor

CB₁ and CB₂ structures.

cannabinoid receptor 1 (brain)
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
Orthologs	7273
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
Orthologs	1389
RefSeq	NM_001841
UniProt	P34972
Other data
Locus	Chr. 1 p

Cannabinoid receptors, located throughout the body, are part of the Endocannabinoid system which is involved in a variety of physiological processes including appetite, pain-sensation, mood, and memory.

Cannabinoid receptors are of 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 groups of ligands: endocannabinoids, produced by the mammillary body; plant cannabinoids (such as Cannabidiol, produced by the cannabis plant); and synthetic cannabinoids (such as HU-210). All of the endocannabinoids and plant cannabinoids are lipophilic, such as fat soluble compounds.

There are currently two known subtypes of cannabinoid receptors, termed CB₁ and CB₂.^[5][6] The CB₁ receptor is expressed mainly in the brain (central nervous system or "CNS"), but also in the lungs, liver and kidneys. The CB₂ receptor is expressed mainly in the immune system and in hematopoietic cells.^[7] Mounting evidence suggests that there are novel cannabinoid receptors^[8] 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 the G protein-coupled receptor GPR55 in the brain was described.^[9]

The protein sequences of CB₁ and CB₂ receptors are about 44% similar.^[10][11] 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. Subtype selective cannabinoids have been developed which theoretically may have advantages for treatment of certain diseases such as obesity.^[12]

CB₁

Cannabinoid receptor type 1 (CB₁) receptors are thought to be one of 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 post-synaptic 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.^[13]

A 2004 study suggested that the endocannabinoids and their cannabinoid receptors play a major role during pre- and postnatal development.^[14][15] In another recent study a group of researchers combined stochastic optical reconstruction microscopy (STORM) and patch clamp in order to see CB1 distribution on a nano scale with incredible resolution.^[16][17]

CB₂

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. They are also expressed on peripheral nerve terminals. These receptors play a role in antinociception, or the relief of pain. In the brain, they are mainly expressed by microglial cells, where their role remains unclear. While the most likely cellular targets and executors of the CB₂ receptor-mediated effects of endocannabinoids or synthetic agonists are the immune and immune-derived cells (e.g. leukocytes, various populations of T and B lymphocytes, monocytes/macrophages, dendritic cells, mast cells, microglia in the brain, Kupffer cells in the liver, etc.), the number of other potential cellular targets is expanding, now including endothelial and smooth muscle cells, fibroblasts of various origins, cardiomyocytes, and certain neuronal elements of the peripheral or central nervous systems.^[7]

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.^[18][19] 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 anandamide (also known as arachidonoylethanolamide or AEA), initiates directed microglial migration in the CNS through activation of GPR18.^[20] 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.^[9][21] 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 categorized as the CB₃ receptor, and this re-classification may follow in time.^[22] 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,^[23] 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.^[24]

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.^[10]

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).^[25] 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.^[25]

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.

Cardiovascular activity

Recent studies have also suggested that activation of CB₁ receptors in human and rodent cardiomyocytes,^[26][27] coronary artery endothelial and inflammatory cells^[28][29][30] promotes activation of mitogen-activated protein (MAP) kinases p38 and JNK, reactive oxygen species generation, cell death, and cardiovascular inflammatory response both in vitro, as well as in models of heart failure, atherosclerosis and vascular inflammation.^{[26][27][29][30]}

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.^[31]

Cannabinoid treatments

Cannabis preparations have been known as therapeutic agents against various diseases for millennia.^[32] The psychoactive compound tetrahydrocannabinol (THC) was found to be the principal mediator of the effects of cannabis.^[33] Synthetic THC is prescribed today, under the INN dronabinol or the brand name Marinol, 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.^[34] 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.^[35] The pharmacology of these agonists has yet to be described.

Certain tumors, especially gliomas, express CB₂ receptors. CB₂ selective agonists are effective in the treatment of pain, inflammatory diseases (in animal models),^[31][36] osteoporosis^[31] and atherosclerosis.^[37] CB₁ selective antagonists have previously been used for weight reduction and smoking cessation (see Rimonabant). Activation of CB₁ provides neuroprotection after brain injury.^[38]

Ligands

See also: cannabinoid receptor type 1 ligands, cannabinoid receptor type 2 ligands

Binding affinity and selectivity of cannabinoid ligands

	CB1 affinity (Ki)	Efficacy towards CB1	CB2 affinity (Ki)	Efficacy towards CB2	Type	References
Anandamide	78nM	Full agonist	370nM	?	Endogenous
N-Arachidonoyl dopamine	?	Agonist	?	?	Endogenous
2-Arachidonoylglycerol	?	Full agonist	?	?	Endogenous
2-Arachidonyl glyceryl ether	21 nM	Full agonist	480nM	Full agonist	Endogenous
Δ-9-Tetrahydrocannabinol	10nM	Partial agonist	24nM	Partial agonist	Phytogenic	[39][39]
EGCG	33.6μM	Agonist	>50μM	?	Phytogenic
Yangonin	0.72 μM	?	> 10 μM	?	Phytogenic	[40]
AM-1221	52.3nM	Agonist	0.28nM	Agonist	Synthetic	[41]
AM-1235	1.5nM	Agonist	20.4nM	Agonist	Synthetic	[42]
AM-2232	0.28nM	Agonist	1.48nM	Agonist	Synthetic	[42]
UR-144	150nM	Full agonist	1.8nM	Full agonist	Synthetic	[43]
JWH-007	9.0nM	Agonist	2.94nM	Agonist	Synthetic	[44]
JWH-015	383nM	Agonist	13.8nM	Agonist	Synthetic	[44]
JWH-018	9.00 ± 5.00 nM	Full agonist	2.94 ± 2.65 nM	Full agonist	Synthetic	[44]

See also

• Cannabinoid receptor antagonist
• Endocannabinoid enhancer
• Endocannabinoid reuptake inhibitor
• Cannabidiol
• Effects of cannabis

References

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External links

• Cannabinoid Receptors at the US National Library of Medicine Medical Subject Headings (MeSH)
• The Endocannabinoid System Network (ECSN) - CB₁ receptor
• "Cannabinoid Receptors". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.