Cannabinoid receptors, located throughout the body, are part of theendocannabinoid system of vertebrates– a class ofcell membranereceptors in theG 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 ofligands:
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 andstereo-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 ofendocannabinoids and endocannabinoid signaling in general (involving targets other than CB1/2-type receptors) occur throughout the animal kingdom.[13]
Cannabinoid receptor type 1 (CB1) receptors are thought to be one of the most widelyexpressed Gαi protein-coupled receptors in the brain. One mechanism through which they function is endocannabinoid-mediateddepolarization-induced suppression of inhibition, a very common form ofretrograde signaling, in which the depolarization of a single neuron induces a reduction inGABA-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 novolipogenesis.[21]
CB2 receptors are expressed onT cells of theimmune system, onmacrophages andB cells, inhematopoietic cells, and in the brain and CNS (2019).[22] They also have a function inkeratinocytes. They are also expressed on peripheralnerve terminals. These receptors play a role inantinociception, or the relief ofpain. In the brain, they are mainly expressed bymicroglial 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).[8]
The existence of additional cannabinoid receptors has long been suspected, due to the actions of compounds such asabnormal cannabidiol that produce cannabinoid-like effects onblood pressure andinflammation, yet do not activate either CB1 or CB2.[23][24] Recent research strongly supports the hypothesis that theN-arachidonoylglycine (NAGly) receptorGPR18 is the molecular identity of the abnormal cannabidiol receptor and additionally suggests that NAGly, the endogenous lipid metabolite ofanandamide (also known as arachidonoylethanolamide or AEA), initiates directedmicroglial migration in the CNS through activation ofGPR18.[25] Other molecular biology studies have suggested that the orphan receptorGPR55 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.[26][27] 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.[28] However this is complicated by the fact that another possible cannabinoid receptor has been discovered in thehippocampus, although its gene has not yet been cloned,[29] 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,[30] while thePPAR family of nuclear hormone receptors can also respond to certain types of cannabinoid.[31]
Cannabinoid receptors are activated by cannabinoids, generated naturally inside the body (endocannabinoids) or introduced into the body ascannabis or a relatedsynthetic compound.[10] Similar responses are produced when introduced in alternative methods, only in a more concentrated form than what is naturally occurring.
Separation between the therapeutically undesirable psychotropic effects, and the clinically desirable ones, however, has not been reported withagonists that bind to cannabinoid receptors.THC, as well as the two majorendogenous compounds identified so far that bind to the cannabinoid receptors —anandamide and2-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 affectneurodevelopment nor cause lifelong cognitive, behavioral, or functional abnormalities, but it may predispose offspring to abnormalities incognition 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]
^abLatek D, Kolinski M, Ghoshdastider U, Debinski A, Bombolewski R, Plazinska A, et al. (September 2011). "Modeling of ligand binding to G protein coupled receptors: cannabinoid CB1, CB2 and adrenergic β 2 AR".Journal of Molecular Modeling.17 (9):2353–66.doi:10.1007/s00894-011-0986-7.PMID21365223.S2CID28365397.
^Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, et al. (June 2002). "International Union of Pharmacology. XXVII. Classification of cannabinoid receptors".Pharmacological Reviews (Review).54 (2):161–202.doi:10.1124/pr.54.2.161.PMID12037135.S2CID8259002.
^abMechoulam R, Fride E (1995). "The unpaved road to the endogenous brain cannabinoid ligands, the anandamides". In Pertwee RG (ed.).Cannabinoid receptors (Review). Boston: Academic Press. pp. 233–258.ISBN978-0-12-551460-6.
^Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, et al. (December 1992). "Isolation and structure of a brain constituent that binds to the cannabinoid receptor".Science.258 (5090):1946–9.Bibcode:1992Sci...258.1946D.doi:10.1126/science.1470919.PMID1470919.
^McHugh D, Tanner C, Mechoulam R, Pertwee RG, Ross RA (February 2008). "Inhibition of human neutrophil chemotaxis by endogenous cannabinoids and phytocannabinoids: evidence for a site distinct from CB1 and CB2".Molecular Pharmacology.73 (2):441–50.doi:10.1124/mol.107.041863.PMID17965195.S2CID15182303.
^Richardson KA, Hester AK, McLemore GL (2016). "Prenatal cannabis exposure - The "first hit" to the endocannabinoid system". review.Neurotoxicology and Teratology.58:5–14.doi:10.1016/j.ntt.2016.08.003.PMID27567698.S2CID5656802.
^Korte G, Dreiseitel A, Schreier P, Oehme A, Locher S, Geiger S, et al. (January 2010). "Tea catechins' affinity for human cannabinoid receptors".Phytomedicine.17 (1):19–22.doi:10.1016/j.phymed.2009.10.001.PMID19897346.
^Ligresti A, Villano R, Allarà M, Ujváry I, Di Marzo V (August 2012). "Kavalactones and the endocannabinoid system: the plant-derived yangonin is a novel CB₁ receptor ligand".Pharmacological Research.66 (2):163–9.doi:10.1016/j.phrs.2012.04.003.PMID22525682.
^abUS patent 7241799, Makriyannis A, Deng H, "Cannabimimetic indole derivatives", granted 2007-07-10
^Frost JM, Dart MJ, Tietje KR, Garrison TR, Grayson GK, Daza AV, et al. (January 2010). "Indol-3-ylcycloalkyl ketones: effects of N1 substituted indole side chain variations on CB(2) cannabinoid receptor activity".Journal of Medicinal Chemistry.53 (1):295–315.doi:10.1021/jm901214q.PMID19921781.
^abcAung MM, Griffin G, Huffman JW, Wu M, Keel C, Yang B, et al. (August 2000). "Influence of the N-1 alkyl chain length of cannabimimetic indoles upon CB(1) and CB(2) receptor binding".Drug and Alcohol Dependence.60 (2):133–40.doi:10.1016/S0376-8716(99)00152-0.PMID10940540.
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