Gennequin, Benjamin: The cannabinoid receptor 2: from mouse to human. - Bonn, 2015. - Dissertation, Rheinische Friedrich-Wilhelms-Universität Bonn.
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author = {{Benjamin Gennequin}},
title = {The cannabinoid receptor 2: from mouse to human},
school = {Rheinische Friedrich-Wilhelms-Universität Bonn},
year = 2015,
month = may,

note = {The endocannabinoid system (ECS) regulates numerous cellular and physiological processes. Nowadays, the system comprises two G protein-coupled receptors named CB1 and CB2 receptor, and the endogenous ligands anandamide (N-arachidonoylethanolamide: AEA) and 2-arachidonylglycerol (2-AG). The CB1 receptor is mainly expressed in the central nervous system, whereas the CB2 receptor is mainly expressed by peripheral cells including immune and bone cells. Unlike the CB1 receptor, CB2 receptor activation does not induce psychoactive negative effects. Together with its expression pattern, the CB2 receptor thus offers a great potential for the treatment of different immune related diseases. The CB2 receptor became a target of choice for the development of new drugs.
A genetic variation within the human gene coding for the CB2 receptor was discovered ten years ago. This genetic variation results in the amino acid exchange from glutamine to arginine at protein position 63 (Q63R), which is localized in the first intracellular loop of the G protein. As a consequence, the signaling activity of the receptor is generally reduced. To address the functional differences between these human variants of the CB2 receptor in vivo, humanized targeting vectors were generated and subsequently used for the generation of chimeric mice by injecting targeted ES cells into blastocysts. Due to the lack of germ-line transmission, new engineering technologies (CRISPR/Cas9 system and TALENs) were designed and tested for their ability to target the Cnr2 locus. The study presented here revealed that applying the CRISPR/Cas9 technology tremendously improved the homologous recombination efficiency in ES cells. In order to assess the functional differences between the human CB2 receptor variants in vitro, recombinant viral vectors were developed using the innate ability of lentiviruses to deliver genetic material into non-dividing cells. Due the low transduction efficiencies measured in bone marrow-derived macrophages (BMMs) for all viral vectors generated, lentiviruses were not further used during the study.
Since its discovery, CB2 receptor activation has been shown to inhibit activation, cell motility and secretion of inflammatory mediators in different kinds of immune cells. In this study, the anti-inflammatory role played by murine CB2 receptor activation was analysed in BMMs. Different pro- and anti-inflammatory activation states of BMMs were induced and characterized. Under pro-inflammatory conditions, CB2 activation had no effect on pro-inflammatory cytokine (TNFα) release. Gene expression analysis revealed that genes encoding cannabinoid receptors are differentially regulated upon stimulation with different combination of pro-inflammatory substances. Finally, CB2 receptor activation with different agonists did not modulate the phagocytic activity of zymosan particles by BMMs. Hence, the data presented here could not clearly confirm an anti-inflammatory role of murine CB2 receptor in BMMs.},

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