Cannabinoid receptor 2

The CB2 receptor is encoded by the CNR2 gene. Approximately 360 amino acids comprise the human CB2 receptor, making it somewhat shorter than the 473-amino-acid-long CB1 receptor. a glycosylated N-terminus, and an intracellular C-terminus. Based on computer modeling, ligand interactions with CB2 receptor residues S3.31 and F5.46 appears to determine differences between CB1 and CB2 receptor selectivity. In CB2 receptors, lipophilic groups interact with the F5.46 residue, allowing them to form a hydrogen bond with the S3.31 residue. These interactions induce a conformational change in the receptor structure, which triggers the activation of various intracellular signaling pathways. Further research is needed to determine the exact molecular mechanisms of signaling pathway activation. == Mechanism ==

Like the CB1 receptors, CB2 receptors inhibit the activity of adenylyl cyclase through their Gi/Goα subunits. CB2 can also couple to stimulatory Gαs subunits leading to an increase of intracellular cAMP, as has been shown for human leukocytes. Through their Gβγ subunits, CB2 receptors are also known to be coupled to the MAPK-ERK pathway, a complex and highly conserved signal transduction pathway, which regulates a number of cellular processes in mature and developing tissues. Activation of the MAPK-ERK pathway by CB2 receptor agonists acting through the Gβγ subunit ultimately results in changes in cell migration. Five recognized cannabinoids are produced endogenously: arachidonoylethanolamine (anandamide), 2-arachidonoyl glycerol (2-AG), 2-arachidonyl glyceryl ether (noladin ether), virodhamine, Many of these ligands appear to exhibit properties of functional selectivity at the CB2 receptor: 2-AG activates the MAPK-ERK pathway, while noladin inhibits adenylyl cyclase. == Expression ==

Dispute Originally it was thought that the CB2 receptor was only expressed in peripheral tissue while the CB1 receptor is the endogenous receptor on neurons. Recent work with immunohistochemical staining has shown expression within neurons. Subsequently, it was shown that CB2 knock out mice produced the same immunohistochemical staining, indicating the presence of the CB2 receptor where none was expressed. This has created a long history of debate as to whether the CB2 receptor is expressed in the CNS. A new mouse model was described in 2014 that expresses a fluorescent protein whenever CB2 is expressed within a cell. This has the potential to resolve questions about the expression of CB2 receptors in various tissues. Immune system Initial investigation of CB2 receptor expression patterns focused on the presence of CB2 receptors in the peripheral tissues of the immune system, These receptors were localized on immune cells such as monocytes, macrophages, B-cells, and T-cells. Unlike the CB1 receptor, in the brain, CB2 receptors are found primarily on microglia. The CB2 receptor is expressed in some neurons within the central nervous system (e.g.; the brainstem), but the expression is very low. CB2s are expressed on some rat retinal cell types. Functional CB2 receptors are expressed in neurons of the ventral tegmental area and the hippocampus, arguing for a widespread expression and functional relevance in the CNS and in particular in neuronal signal transmission. Gastrointestinal system CB2 receptors are also found throughout the gastrointestinal system, where they modulate intestinal inflammatory response. Thus, CB2 receptor is a potential therapeutic target for inflammatory bowel diseases, such as Crohn's disease and ulcerative colitis. The role of endocannabinoids, as such, play an important role in inhibiting unnecessary immune action upon the natural gut flora. Dysfunction of this system, perhaps from excess FAAH activity, could result in IBD. CB2 activation may also have a role in the treatment of irritable bowel syndrome. Cannabinoid receptor agonists reduce gut motility in IBS patients. Peripheral nervous system Application of CB2-specific antagonists has found that these receptors are also involved in mediating analgesic effects in the peripheral nervous system. However, these receptors are not expressed by nociceptive sensory neurons, and at present are believed to exist on an undetermined, non-neuronal cell. Possible candidates include mast cells, known to facilitate the inflammatory response. Cannabinoid mediated inhibition of these responses may cause a decrease in the perception of noxious-stimuli. == Function ==

Immune system Primary research on the functioning of the CB2 receptor has focused on the receptor's effects on the immunological activity of leukocytes. To be specific, this receptor has been implicated in a variety of modulatory functions, including immune suppression, induction of apoptosis, and induction of cell migration. CB2 also signals via Gαs and increases intracellular cAMP in human leukocytes, leading to induction of interleukins 6 and 10. Consistent with these findings are studies that demonstrate increased CB2 receptor expression in the spinal cord, dorsal root ganglion, and activated microglia in the rodent neuropathic pain model, as well as on human hepatocellular carcinoma tumor samples. CB2 receptors have also been implicated in the regulation of homing and retention of marginal zone B cells. A study using knock-out mice found that CB2 receptor is essential for the maintenance of both MZ B cells and their precursor T2-MZP, though not their development. Both B cells and their precursors lacking this receptor were found in reduced numbers, explained by the secondary finding that 2-AG signaling was demonstrated to induce proper B cell migration to the MZ. Without the receptor, there was an undesirable spike in the blood concentration of MZ B lineage cells and a significant reduction in the production of IgM. While the mechanism behind this process is not fully understood, the researchers suggested that this process may be due to the activation-dependent decrease in cAMP concentration, leading to reduced transcription of genes regulated by CREB, indirectly increasing TCR signaling and IL-2 production. Specifically, the CB2 agonist JWH-015 was shown to induce macrophages to remove native beta-amyloid protein from frozen human tissues. In patients with Alzheimer's disease, beta-amyloid proteins form aggregates known as senile plaques, which disrupt neural functioning. Changes in endocannabinoid levels and/or CB2 receptor expressions have been reported in almost all diseases affecting humans, ranging from cardiovascular, gastrointestinal, liver, kidney, neurodegenerative, psychiatric, bone, skin, autoimmune, lung disorders to pain and cancer. The prevalence of this trend suggests that modulating CB2 receptor activity by either selective CB2 receptor agonists or inverse agonists/antagonists depending on the disease and its progression holds unique therapeutic potential for these pathologies == Ligands ==

Many selective ligands for the CB2 receptor are now available. Agonists • Minocycline • AM404 Partial agonists • GW-405,833 Unspecified efficacy agonists • AM-1241 • HU-308 • JWH-015 • JWH-133 • L-759,633 • L-759,656 Herbal • Echinacea purpurea Inverse agonists • AM-630 • BML-190 • JTE-907 • SR-144,528 • APD371 == Binding affinities ==

=== Paralogues === Source: • CNR1 • GPR12 • GPR6 • S1PR1 • S1PR4 • S1PR3 • S1PR5 • S1PR2 • LPAR1 • GPR3 • LPAR3 • LPAR2 • MC4R • MC5R • GPR119 • MC1R • MC3R • MC2R == References ==