## 2 Endocannabinoid System (ECS)
### ECS--Cannabinoid Receptors
#### 2.1.2 ECS--CB2 Receptors  
The CB2 receptor, which in humans is encoded by the _CNR2_ gene, was initially isolated from HL60 cells, a human promylocytic leukemic cell line [7]. While CB1 receptors are primarily associated with the nervous system, CB2 receptors are mainly found on cells within the immune system and are involved in immunomodulation [4]. However, recent findings indicate that CB2 receptors are also expressed in the brain, by microglial cells and even neurons [8; 16]. Their expression primarily occurs in lymphoid organs, including lymph nodes, spleen, thymus, and tonsils, as well as blood cells, mature B lymphocytes and macrophages, and in smaller amounts on mast cells, NK cells, CD4+, and CD8+ lymphocytes. It is also present in the bones, where its expression has been found in bone marrow mesenchymal stem cells [17] as well as osteoclasts [18]. Interestingly, according to some reports, the CB2 receptor was also found in the autonomic nervous system, where it was found in presynaptic membranes, but its function here has not been fully elucidated [19]. This receptor has been associated with diverse regulatory roles, encompassing the control of cell movement, phagocytosis, and primarily, the inhibition of immune cell activity. This immune-suppressive effect results from the reduction in the release of pro-inflammatory cytokines (such as TNF-a, IL-1b, IL-1 Ra), the inhibition of cyclooxygenase-2 (COX-2) production, and the suppression of CD40 expression [4]. Regarding the GIT, CB2 receptors are primarily located on immune cells within the gut-associated lymphoid tissue (GALT), which is connected to the modulation of inflammatory responses in the intestines. CB2 receptors are also present on the neurons of ENS and epithelial cells, especially in pathological conditions [20]. Hence, the CB2 receptor presents itself as a promising focus for addressing inflammatory bowel diseases through therapeutic approaches, which is the main subject of this paper.  
Some authors claim that GPR55, GPR119, and GPR18 should be implicated as novel cannabinoid receptors, as they can be agonized by cannabinoids [21; 22]. The determination of specific biological functions of these receptors, however, requires further investigation.  
Three-dimensional schematics of human cannabinoid receptor types 1 and 2 are shown in Figure 1.  
Figure 1: **Three-dimensional visualization of human type 1 and type 2 cannabinoid receptors based on crystallographic data.** CB1 and CB2 receptors are metabotropic receptors coupled with  
Gi/o proteins. These receptors consist of a single polypeptide chain with seven hydrophobic transmembrane domains traversing the cell membrane. These hydrophobic domains contain binding sites for ligands. Intracellular loops are the site of interaction with the G protein. Homology between CB receptors is approximately 44%. Crystallographic data published by [PERSON] et al. were used to visualize the CB1 receptor [23], and crystallographic data by [PERSON] et al. were taken to visualize the structure of the CB2 receptor [24]. Visualization was done in \"PDBe-KB 3D viewer online\".  
The schematics representing distribution of CB1 and CB2 receptors in the body are shown in Figure 2.