Cannabinoid receptor

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CB1 and CB2 structures
Chr. 6 q14-q15
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Cannabinoid receptors, located throughout the body, are part of the endocannabinoid system of vertebrates– a class of cell membrane receptors in the G protein-coupled receptor superfamily.[1][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:

All endocannabinoids and phytocannabinoids are

lipophilic
.

There are two known subtypes of cannabinoid receptors, termed

hematopoietic cells,[8] and in parts of the brain.[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%.[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.[12]

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.[13]

Discovery

The existence of cannabinoid

cannabinoid receptor type 2 or CB2.[15]

A

endocannabinoid system in the brain and peripheral nervous system, anandamide (from 'ananda', Sanskrit for 'bliss'), was first characterized in 1992,[18][19][20] 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.[15][18]

Types

CB1

Main article:
Cannabinoid receptor type 1

Cannabinoid receptor type 1 (CB1) receptors are thought to be one of the most widely

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.[medical citation needed
]

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.[21]

CB2

Main article:
Cannabinoid receptor type 2

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).[8]

Other

The existence of additional cannabinoid receptors has long been suspected, due to the actions of compounds such as

PPAR family of nuclear hormone receptors can also respond to certain types of cannabinoid.[31]

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] 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

adenylate cyclase via stimulatory Gαs alongside the classical Gαi signalling, and induces ERK, p38 and pCREB pathways.[33]

Separation between the therapeutically undesirable psychotropic effects, and the clinically desirable ones, however, has not been reported with

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.

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.[34] 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.[35]

Cannabinoid treatments

Main article: Medical cannabis

Synthetic

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.[37]

Ligands

Further information:
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 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 [38]
EGCG
 33,600 nM Agonist >50,000 nM ? Phytogenic [39]
Yangonin 720 nM ? >10,000 nM ? 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

References

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  37. ^ "Sativex Oromucosal Spray - Summary of Product Characteristics". UK Electronic Medicines Compendium. March 2015. Archived from the original on 2016-08-22. Retrieved 2017-10-09.
  38. ^ "PDSP Database - UNC". Archived from the original on 8 November 2013. Retrieved 11 June 2013.
  39. PMID 19897346
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  41. Makriyannis A
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  42. ^ a b US patent 7241799, Makriyannis A, Deng H, "Cannabimimetic indole derivatives", granted 2007-07-10 
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External links
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