Cannabinoid receptor

File:Cb1 cb2 structure.png

CB₁ and CB₂ structures

Cannabinoid receptors, located throughout the body, are part of the endocannabinoid system of vertebratesTemplate:Ndash a class of cell membrane receptors in the G protein-coupled receptor superfamily.<ref name="pmid12432948"/><ref name="pmid18426493"/><ref name="pmid19273110"/><ref>Template:Cite journal</ref> As is typical of G protein-coupled receptors, the cannabinoid receptors contain seven transmembrane spanning domains.<ref name="pmid7556170"/> Cannabinoid receptors are activated by three major groups of ligands:

• Endocannabinoids;
• Phytocannabinoids (plant-derived such as tetrahydrocannabinol (THC) produced by cannabis);
• Synthetic cannabinoids (such as HU-210).

All endocannabinoids and phytocannabinoids are lipophilic.

There are two known subtypes of cannabinoid receptors, termed CB₁ and CB₂.<ref name="pmid2165569"/><ref name="pmid1718258"/> 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, in hematopoietic cells,<ref name="pmid21295074">Template:Cite journal</ref> and in parts of the brain.<ref name="pmid30611802">Template:Cite journal</ref>

The protein sequences of CB₁ and CB₂ receptors are about 44% similar.<ref name=latek>Template:Cite journal</ref><ref name="pmid7689702"/> When only the transmembrane regions of the receptors are considered, amino acid similarity between the two receptor subtypes is approximately 68%.<ref name="pmid7556170"/> 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.<ref name="pmid17148745">Template:Cite journal</ref>

Enzymes involved in biosynthesis/inactivation of endocannabinoids and endocannabinoid signaling in general (involving targets other than CB1/2-type receptors) occur throughout the animal kingdom.<ref>Template:Cite journal</ref>

Discovery

The existence of cannabinoid receptors in the brain was discovered from in vitro studies in the 1980s, with the receptor designated as the cannabinoid receptor type 1 or CB1.<ref name="elphick">Template:Cite journal</ref><ref name="Pertwee_2006">Template:Cite journal</ref> The DNA sequence that encodes a G-protein-coupled cannabinoid receptor in the human brain was identified and cloned in 1990.<ref>Template:Cite journal</ref><ref name="Howlett_2002">Template:Cite journal</ref> These discoveries led to determination in 1993 of a second brain cannabinoid receptor named cannabinoid receptor type 2 or CB2.<ref name=Pertwee_2006/>

A neurotransmitter for a possible endocannabinoid system in the brain and peripheral nervous system, anandamide (from 'ananda', Sanskrit for 'bliss'), was first characterized in 1992,<ref name="unpaved">Template:Cite book</ref><ref>Template:Cite journal</ref><ref name="Hanus_2007">Template:Cite journal</ref> followed by discovery of other fatty acid neurotransmitters that behave as endogenous cannabinoids having a low-to-high range of efficacy for stimulating CB1 receptors in the brain and CB2 receptors in the periphery.<ref name=Pertwee_2006/><ref name=unpaved/>

Types

CB₁

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Cannabinoid receptor type 1 (CB₁) receptors are thought to be one of the most widely expressed G_αi protein-coupled receptors in the brain. One mechanism through which they function is endocannabinoid-mediated depolarization-induced suppression of inhibition, a very common form of retrograde signaling, 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 due to limited presynaptic calcium ions entry.Template:Medcn

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.<ref name="pmid15864349"/>

CB₂

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CB₂ receptors are expressed on T cells of the immune system, on macrophages and B cells, in hematopoietic cells, and in the brain and CNS (2019).<ref>Template:Cite book</ref> 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, astrocytes, 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 (2011).<ref name="pmid21295074"/>

Other

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.<ref name="pmid10570211"/><ref name="pmid17965195"/> 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.<ref name="pmid20346144"/> 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.<ref name="pmid17876302"/><ref name="pmid17704827"/> 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.<ref name="pmid16517404"/> 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,<ref name="pmid18482429"/> 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,<ref name="pmid17906678"/> while the PPAR family of nuclear hormone receptors can also respond to certain types of cannabinoid.<ref>Template:Cite journal</ref>

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.<ref name=latek /> Similar responses are produced when introduced in alternative methods, only in a more concentrated form than what is naturally occurring.

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).<ref name="pmid16109430"/> 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.<ref name="pmid16109430"/> For example, in human primary leukocytes CB₂ displays a complex signalling profile, activating adenylate cyclase via stimulatory G_αs alongside the classical G_αi signalling, and induces ERK, p38 and pCREB pathways.<ref name="Saroz _2019">Template:Cite journal</ref>

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.

Prenatal cannabis exposure (PCE) has been shown to perturb the fetal endogenous cannabinoid signaling system. This perturbation has not been shown to directly affect neurodevelopment nor cause lifelong cognitive, behavioral, or functional abnormalities, but it may predispose offspring to abnormalities in cognition and altered emotionality from post-natal factors.<ref name="pmid27567698">Template:Cite journal</ref> Additionally, PCE may alter the wiring of brain circuitry in foetal development and cause significant molecular modifications to neurodevelopmental programs that may lead to neurophysiological disorders and behavioural abnormalities.<ref name="Calvigioni_2014">Template:Cite journal</ref>

Cannabinoid treatments

{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}} Synthetic tetrahydrocannabinol (THC) is prescribed under the INN dronabinol or the brand name Marinol, to treat vomiting and for enhancement of appetite, mainly in people with AIDS as well as for refractory nausea and vomiting in people undergoing chemotherapy.<ref>Template:Cite journal</ref> Use of synthetic THC is becoming more common as the known benefits become more prominent within the medical industry. THC is also an active ingredient in nabiximols, a specific extract of Cannabis that was approved as a botanical drug in the United Kingdom in 2010 as a mouth spray for people with multiple sclerosis to alleviate neuropathic pain, spasticity, overactive bladder, and other symptoms.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Ligands

Binding affinity and selectivity of cannabinoid ligands:

	CB1 affinity (Ki)	Efficacy towards CB1	CB2 affinity (Ki)	Efficacy towards CB2	Type	References
Anandamide	78nM	Partial 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	citation	CitationClass=web }}</ref>
EGCG	33,600 nM	Agonist	>50,000 nM	?	Phytogenic	<ref name="ecgc">Template:Cite journal</ref>
Yangonin	720 nM	?	>10,000 nM	?	Phytogenic	<ref>Template:Cite journal</ref>
AM-1221	52.3nM	Agonist	0.28nM	Agonist	Synthetic	<ref name="dude">Template:Ref patent2</ref>
AM-1235	1.5nM	Agonist	20.4nM	Agonist	Synthetic	<ref name="like">Template:Ref patent2</ref>
AM-2232	0.28nM	Agonist	1.48nM	Agonist	Synthetic	<ref name="like"/>
UR-144	150nM	Full agonist	1.8nM	Full agonist	Synthetic	<ref name="myhandsareamazing">Template:Cite journal</ref>
JWH-007	9.0nM	Agonist	2.94nM	Agonist	Synthetic	<ref name="Aung_2000">Template:Cite journal</ref>
JWH-015	383nM	Agonist	13.8nM	Agonist	Synthetic	<ref name="Aung_2000"/>
JWH-018	9.00 ± 5.00 nM	Full agonist	2.94 ± 2.65 nM	Full agonist	Synthetic	<ref name="Aung_2000"/>

See also

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

External links

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