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The CB2 Receptor and Its Role As a Regulator of Inflammation

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The CB2 Receptor and Its Role As a Regulator of Inflammation Cell. Mol. Life Sci. DOI 10.1007/s00018-016-2300-4 Cellular and Molecular Life Sciences REVIEW The CB2 receptor and its role as a regulator of inflammation 1 1 1 1 Caroline Turcotte • Marie-Rene´e Blanchet • Michel Laviolette • Nicolas Flamand Received: 30 March 2016 / Revised: 20 June 2016 / Accepted: 27 June 2016 Ó The Author(s) 2016. This article is published with open access at Springerlink.com Abstract The CB2 receptor is the peripheral receptor for Abbreviations cannabinoids. It is mainly expressed in immune tissues, 2-AG 2-Arachidonoyl-glycerol highlighting the possibility that the endocannabinoid sys- AA Arachidonic acid tem has an immunomodulatory role. In this respect, the AEA N-Arachidonoyl-ethanolamide CB2 receptor was shown to modulate immune cell func- AM1241 (2-Iodo-5-nitrophenyl)-(1-(1- tions, both in cellulo and in animal models of inflammatory methylpiperidin-2-ylmethyl)-1H-indol- diseases. In this regard, numerous studies have reported 3-yl)methanone that mice lacking the CB2 receptor have an exacerbated AM630 6-Iodo-2-methyl-1-[2-(4- inflammatory phenotype. This suggests that therapeutic morpholinyl)ethyl]-1H-indol-3-yl](4- strategies aiming at modulating CB2 signaling could be methoxyphenyl)methanone promising for the treatment of various inflammatory con- CB65 N-Cyclohexyl-7-chloro-1-[2-(4- ditions. Herein, we review the pharmacology of the CB2 morpholinyl)ethyl]quinolin-4(1H)-one- receptor, its expression pattern, and the signaling pathways 3-carboxamide induced by its activation. We next examine the regulation cAMP Cyclic adenosine monophosphate of immune cell functions by the CB2 receptor and the CBD Cannabidiol evidence obtained from primary human cells, immortalized CBG Cannabigerol cell lines, and animal models of inflammation. Finally, we CBN Cannabinol discuss the possible therapies targeting the CB2 receptor COX Cyclooxygenase and the questions that remain to be addressed to determine CP 55,940 (–)-Cis-3-[2-hydroxy-4-(1,1- whether this receptor could be a potential target to treat dimethylheptyl)phenyl]-trans-4- inflammatory disease. (3-hydroxypropyl)cyclohexanol D9-THC (–)-D9-Tetrahydrocannabinol Keywords CB2 receptor Á Cannabinoid Á ERK-1/2 Extracellular signal-regulated kinases-1/2 Endocannabinoid Á Inflammation Á Leukocytes FAAH Fatty acid amide hydrolase GFP Green fluorescent protein GIRK G-protein-coupled inwardly rectifying potassium (channel) GP 1a N-(Piperidin-1-yl)-1-(2,4- dichlorophenyl)-1,4-dihydro- & Nicolas Flamand 6-methylindeno[1,2-c]pyrazole- nicolas.fl[email protected] 3-carboxamide GP 2a N-Cyclohexyl-1-(2,4-dichlorophenyl)- 1 Centre de recherche de l’Institut universitaire de cardiologie 1,4-dihydro-6-methylindeno[1,2- et de pneumologie de Que´bec, De´partement de me´decine, Faculte´ de me´decine, Universite´ Laval, Quebec, QC c]pyrazole-3-carboxamide G1V 4G5, Canada GPCR G-protein-coupled-receptor 123 C. Turcotte et al. HU-210 3-(1,10-Dimethylheptyl)-6aR,7,10,10aR- expressed in the central nervous system, namely CB1. tetrahydro-1-hydroxy-6,6-dimethyl-6H- The identification of a receptor that is selectively acti- dibenzo[b,d]pyran-9-methanol vated by cannabinoids suggested that the human body HU-308 4-[4-(1,1-Dimethylheptyl)-2,6- synthesizes at least one natural ligand for this receptor. dimethoxyphenyl]-6,6- This hypothesis was confirmed by the discovery of two dimethylbicyclo[3.1.1]hept-2-ene- high-affinity ligands for the CB1 receptor: arachidonoyl- 2-methanol ethanolamide (AEA) [1] and 2-arachidonoyl-glycerol (2- IP3 Inositol 1,4,5-trisphosphate AG) [2]. As these novel lipid mediators were uncovered, JTE 907 N-(1,3-Benzodioxol-5-ylmethyl)-1, a second cannabinoid receptor (CB2) was being cloned 2-dihydro-7-methoxy-2-oxo-8- and characterized. Its expression profile among tissues (pentyloxy)-3-quinolinecarboxamide was found to be distinct from that of CB1. It was pri- JWH 015 (2-Methyl-1-propyl-1H-indol-3-yl)-1- marily found in immune cells and was initially not naphthalenyl-methanone detected in the brain, although this was later proven JWH 133 (6aR,10aR)-3-(1,1-Dimethylbutyl)- incorrect by several studies. In light of these findings, the 6a,7,10,10a-tetrahydro-6,6,9-trimethyl- CB2 receptor was postulated to be responsible for the 6H-dibenzo[b,d]pyran immunomodulatory effects of cannabinoids and endo- L-759,633 (6aR,10aR)-3-(1,1-Dimethylheptyl)- cannabinoids. In the past two decades, this hypothesis 6a,7,10,10a-tetrahydro-1-methoxy-6,6, was tested in a wide array of cellular and animal models. 9-trimethyl-6H-dibenzo[b,d]pyran This article offers a comprehensive review of the evi- L-759,656 (6aR,10aR)-3-(1,1-Dimethylheptyl)- dence that was gathered in these studies, with a focus on 6a,7,8,9,10,10a-hexahydro-1-methoxy- peripheral inflammation. The CB2 receptor’s potential as 6,6-dimethyl-9-methylene-6H- a therapeutic target in inflammatory disease is also dibenzo[b,d]pyran discussed. LOX Lipoxygenase MAG Monoacylglycerol MAPK Mitogen-activated protein kinases Cloning of the CB2 receptor NADA N-Arachidonoyl-dopamine PI3K Phosphoinositide 3-kinase The non-psychoactive effects of cannabinoids were ini- PKC Protein kinase C tially believed to be mediated either centrally or through PLC Phospholipase C their interaction with non-receptor proteins. Although PTX Pertussis toxin there are phytocannabinoids that exert non-psychoactive SER 601 N-(Adamant-1-yl)-6-isopropyl-4-oxo- effects without binding to CB2 receptor [e.g., cannabidiol 1-pentyl-1,4-dihydroquinoline-3- (CBD), cannabigerol (CBG)], discovering the latter carboxamide explained many of the peripheral effects of cannabinoids. WIN 55,212-2 [(3R)-2,3-Dihydro-5-methyl-3-(4- Munro et al. cloned the human CB2 receptor in 1993 from morpholinylmethyl)pyrrolo[1,2,3-de]- the promyelocytic leukaemic cell line HL-60 [3]. To 1,4-benzoxazin-6-yl]-1-naphthalenyl- achieve this, cells were treated with dimethylformamide methanone, monomethanesulfonate to induce granulocyte differentiation, a cDNA library was SR141716A N-(Piperidin-1-yl)-5-(4-chlorophenyl)- prepared, polymerase chain reaction (PCR) was per- 1-(2,4-dichlorophenyl)-4-methyl-1H- formed using degenerated primers, and the amplification pyrazole-3-carboxamide hydrochloride products were cloned and sequenced. One of the clones SR144528 5-(4-Chloro-3-methylphenyl)-1-[(4- showed homology to the G-protein-coupled-receptor methylphenyl)methyl]-N-[(1S,2S,4R)- (GPCR) family and was related to the CB1 receptor. The 1,3,3-trimethylbicyclo[2.2.1]hept-2-yl]- protein encoded by this sequence was found to have 44 % 1H-pyrazole-3-carboxamide homology with the CB1 receptor. This homology increased to 68 % when only the transmembrane portion was considered. Binding assays showed that this receptor had high affinity for the cannabinoid receptor ligands Introduction WIN 55,212-2 and CP 55,940, as well as the endo- cannabinoid AEA and the phytocannabinoid D9-THC. The The psychotropic effects induced by cannabis promoted authors suggested that the previously described central its widespread use among the population. These effects receptor be named CB1 and that this novel, peripheral are mediated by a cannabinoid receptor that is mainly receptor be named CB2. 123 The CB2 receptor and its role as a regulator of inflammation A few years later, Shire et al. [4] cloned the murine Available tools to study CB2 receptor functions CB2 receptor from a mouse splenocyte cDNA library. They found it to be 82 % homologous to the human CB2 Pharmacological compounds receptor and to have similar affinity for the ligands AEA, CP 55,940, and D9-THC. WIN 55,212-2, however, Synthetic cannabinoids, such as CP 55,940 and WIN bound the mouse CB2 receptor with an affinity six-fold 55,212-2, were already available when the CB2 receptor lower than that documented for human CB2.Thiswas was cloned. They were subsequently shown to be potent followed by the cloning of the rat CB2 receptor by CB2 ligands, but also to lack selectivity, as they activate Brown et al. [5]. The authors also compared the CB1 with comparable efficiency. In this respect, several sequence of their clone with those of the mouse and agonists and antagonists were rapidly developed and made human CB2 receptor and found significant differences in available to the scientific community. The most widely protein length, although these were mainly the conse- used compounds are the agonist JWH 133, and the antag- quence of disparities in carboxyl termini. Amino acid onists SR144528 and AM630. Still, many compounds conservation was highest in the transmembrane regions display good potency and selectivity towards CB2. Table 2 of the three receptors. contains a comprehensive list of those compounds, as well In addition to binding the endocannabinoids AEA and as their binding potency towards human CB2, and in some 2-AG, the CB2 receptor binds many phytocannabinoids. cases, the other receptors they target. The pharmacology of endocannabinoids and that of the CB2 receptor were rigorously reviewed in the past [6, 7]. Knockout mice Table 1 provides a summary of the various endocannabi- noids and phytocannabinoids and their affinity for the The first CB2 receptor-deficient mouse was generated by human CB2 receptor. Buckley et al. in 2000 [32]. The CNR2 gene was Table 1 Binding of endocannabinoids and phytocannabinoids to the human CB2 receptor Ki (nM) Model References Endocannabinoid AEA 371 CHO cells [8] 1940 AtT-20 cells [9] 795 Sf9 cells [10] 3500 CHO cells [10] 2-AG 949 Sf9 cells [10] 650 CHO cells [10] Dihomo-c-LEA 857 AtT-20 cells [9] Oleamide [100,000 HEK-293 cells [11] NADA 12,000b Rat spleen [12] 2-AG-ether [3000a COS-7 cells [13] Phytocannabinoid D9-THC 34.6 CHO cells [8] D8-THC 39.3 Mouse spleen [14] CBN 96.3 CHO cells [8] 301 AtT-20 cells [9] CBD 2680 CHO cells [8] b-Caryophyllene 155 HEK293 cells [15] 3 Ki values were obtained in function of [ H]CP 55,940 displacement unless indicated otherwise NADA N-arachidonoyl-dopamine, CBN cannabinol a [3H]HU-243 b [3H]WIN55212-2 123 C.
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