Cannabinoid receptor: Difference between revisions
Added information about discovery of cannabinoids and receptors |
Reverted good faith edits by Ethel the aardvark: Unencyclopedic, WP:NOTTEXTBOOK; needs a WP:MEDRS review rather than the editor's synthesiis, WP:SYNTH (TW) |
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It appears that cannabinoid receptors are unique to the [[phylum]] [[Chordata]] and, as such, they have a rather restricted [[phylogenetic]] distribution in the animal kingdom. However, enzymes involved in biosynthesis/inactivation of [[endocannabinoid]]s and endocannabinoid signalling in general (involving targets other than CB1/2-type receptors) occur throughout the animal kingdom.<ref>{{citation | author1=Maurice R. Elphick | title=The evolution and comparative neurobiology of endocannabinoid signalling | journal=Philosophical Transactions of the Royal Society of London B | volume=367 | issue=1607 | year=2012 | pages=3201–3215 | doi=10.1098/rstb.2011.0394| pmid=23108540 | pmc=3481536 }}</ref> Although the cannabinoid receptors are unique to Chordates, other organisms are still able to process the endocannabinoids through other techniques. |
It appears that cannabinoid receptors are unique to the [[phylum]] [[Chordata]] and, as such, they have a rather restricted [[phylogenetic]] distribution in the animal kingdom. However, enzymes involved in biosynthesis/inactivation of [[endocannabinoid]]s and endocannabinoid signalling in general (involving targets other than CB1/2-type receptors) occur throughout the animal kingdom.<ref>{{citation | author1=Maurice R. Elphick | title=The evolution and comparative neurobiology of endocannabinoid signalling | journal=Philosophical Transactions of the Royal Society of London B | volume=367 | issue=1607 | year=2012 | pages=3201–3215 | doi=10.1098/rstb.2011.0394| pmid=23108540 | pmc=3481536 }}</ref> Although the cannabinoid receptors are unique to Chordates, other organisms are still able to process the endocannabinoids through other techniques. |
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==Discovery== |
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The existence of cannabinoid receptors in the brains of mammals was first discovered in 1988 <ref>{{cite journal | vauthors = Devane WA1, Dysarz FA 3rd, Johnson MR, Melvin LS, Howlett AC | title = Determination and characterization of a cannabinoid receptor in rat brain | journal = Molecular Pharmacology | publisher = American Society for Pharmacology and Experimental Therapeutics | volume = 34 | issue = 5| pages = 605-613 | date = 1988 | pmid = 2848184 }}</ref>by five scientists at St Louis University Medical School Department of Pharmacology in Missouri USA. Lead authors Allyn Howlett and William Devane and their team tested a biologically active bicyclic cannabinoid analgetic CP-55,940 and found that it would selectively bind to certain P2 membranes and synaptosomes in the brain tissue of rats. |
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In 1990, researchers at the [[National Institute of Mental Health]] in Bethseda Maryland led by Dr Lisa Matsuda in the Laboratory of Cell Biology were able to map the DNA sequence that encodes a G-protein-coupled cannabinoid receptor in the human brain and then clone this receptor. <ref>{{cite journal | vauthors = 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 | date = Aug 9 1990 | pmid = 2165569 | doi = 10.1038/346561a0 }}</ref>. |
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These discoveries prompted a flurry of research which uncovered a second cannabinoid named CB2 which is found throughout the immune and peripheral nervous systems as well as the existence of naturally occurring neurotransmitters in the human body called endocannabinoids. <ref>{{cite journal | vauthors = Elphick MR1, Egertová M | title = The neurobiology and evolution of cannabinoid signalling | journal = Philosophical Transactions of the Royal Society B – Biological Sciences | volume = 356 | issue = 1407| pages = 381-408 | date = Mar 2001 | pmid = 11316486 | doi = 10.1098/rstb.2000.0787 }}</ref>. |
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The endocannabinoid anandamide was uncovered in 1992 by Devane, Hanus and researchers at the [[Hebrew University]] in Jerusalem. <ref>{{cite journal | vauthors = Devane WA1, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, Gibson D, Mandelbaum A, Etinger A, Mechoulam R | title = Isolation and structure of a brain constituent that binds to the cannabinoid receptor | journal = Science | volume = 5090 | issue = 258| pages = 1946-9 | date = Dec 18 1992 | pmid = 1470919 | doi = 10.1126/science.1470919 }}</ref>. This team went on to uncover <ref>{{cite web | author = Melissa Moore | url = https://www.labroots.com/trending/cannabis-sciences/8456/endocannabinoid-system-discovered | title = How the Endocannabinoid System was Discovered | accessdate = 12 August 2019 | date = 5 April 2019 | format = article | publisher = LabRoots}}</ref>a range of other endocannabinoids as well as various G- coupled protein receptors that interact with these endocannabinoids. |
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==CB<sub>1</sub>== |
==CB<sub>1</sub>== |
Revision as of 00:21, 12 August 2019
cannabinoid receptor 1 (brain) | |||||||
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Identifiers | |||||||
Symbol | CNR1 | ||||||
Alt. symbols | CNR | ||||||
NCBI gene | 1268 | ||||||
HGNC | 2159 | ||||||
OMIM | 114610 | ||||||
Orthologs | 7273 | ||||||
RefSeq | NM_033181 | ||||||
UniProt | P21554 | ||||||
Other data | |||||||
Locus | Chr. 6 q14-q15 | ||||||
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cannabinoid receptor 2 (macrophage) | |||||||
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Identifiers | |||||||
Symbol | CNR2 | ||||||
NCBI gene | 1269 | ||||||
HGNC | 2160 | ||||||
OMIM | 605051 | ||||||
Orthologs | 1389 | ||||||
RefSeq | NM_001841 | ||||||
UniProt | P34972 | ||||||
Other data | |||||||
Locus | Chr. 1 p | ||||||
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Part of a series on |
Cannabis |
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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.[1]
Cannabinoid receptors are of a class of cell membrane receptors in the G protein-coupled receptor superfamily.[2][3][4] As is typical of G protein-coupled receptors, the cannabinoid receptors contain seven transmembrane spanning domains.[5] Cannabinoid receptors are activated by three major groups of ligands: endocannabinoids, produced by the mammillary body;[citation needed] plant cannabinoids (such as cannabidiol, produced by the cannabis plant); and synthetic cannabinoids (such as HU-210). All of the endocannabinoids and phytocannabinoids (plant based cannabinoids) are lipophilic, such as fat soluble compounds.
There are currently two known subtypes of cannabinoid receptors, termed CB1 and CB2.[6][7] 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.[8] Mounting evidence suggests that there are novel cannabinoid receptors[9] 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.[10]
The protein sequences of CB1 and CB2 receptors are about 44% similar.[11][12] When only the transmembrane regions of the receptors are considered, amino acid similarity between the two receptor subtypes is approximately 68%.[5] 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.[13]
It appears that cannabinoid receptors are unique to the phylum Chordata and, as such, they have a rather restricted phylogenetic distribution in the animal kingdom. However, enzymes involved in biosynthesis/inactivation of endocannabinoids and endocannabinoid signalling in general (involving targets other than CB1/2-type receptors) occur throughout the animal kingdom.[14] Although the cannabinoid receptors are unique to Chordates, other organisms are still able to process the endocannabinoids through other techniques.
CB1
Cannabinoid receptor type 1 (CB1) receptors are thought to be one of the most widely expressed Gαi 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.
This article needs additional citations for verification. (December 2017) |
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.[15]
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, 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.[8]
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.[16][17] 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.[18] 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.[10][19] 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.[20] 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,[21] 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.,[22] while the PPAR family of nuclear hormone receptors can also respond to certain types of cannabinoid.[23]
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.[11] 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).[24] 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.[24]
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 pertubation 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.[25]. 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.[26]
Cannabinoid treatments
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.[27] 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.[28]
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 | [29][29] |
EGCG | 33.6μM | Agonist | >50μM | ? | Phytogenic | |
Yangonin | 0.72 μM | ? | > 10 μM | ? | Phytogenic | [30] |
AM-1221 | 52.3nM | Agonist | 0.28nM | Agonist | Synthetic | [31] |
AM-1235 | 1.5nM | Agonist | 20.4nM | Agonist | Synthetic | [32] |
AM-2232 | 0.28nM | Agonist | 1.48nM | Agonist | Synthetic | [32] |
UR-144 | 150nM | Full agonist | 1.8nM | Full agonist | Synthetic | [33] |
JWH-007 | 9.0nM | Agonist | 2.94nM | Agonist | Synthetic | [34] |
JWH-015 | 383nM | Agonist | 13.8nM | Agonist | Synthetic | [34] |
JWH-018 | 9.00 ± 5.00 nM | Full agonist | 2.94 ± 2.65 nM | Full agonist | Synthetic | [34] |
See also
- Cannabinoid receptor antagonist
- Endocannabinoid enhancer
- Endocannabinoid reuptake inhibitor
- Cannabidiol
- Effects of cannabis
References
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- ^ Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI (1990). "Structure of a cannabinoid receptor and functional expression of the cloned cDNA". Nature. 346 (6284): 561–4. doi:10.1038/346561a0. PMID 2165569.
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- ^ a b 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): 1092–1101. doi:10.1038/sj.bjp.0707460. PMC 2095107. PMID 17876302.
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External links
- Cannabinoid+Receptors at the U.S. 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.