Cannabinoid receptor type 2

2KI9126912802ENSG00000188822ENSMUSG00000062585P34972P47936NM_001841NM_009924NM_001305278NP_001832NP_001292207NP_034054The cannabinoid receptor type 2, abbreviated as CB2, is a G protein-coupled receptor from the cannabinoid receptor family that in humans is encoded by the CNR2 gene. It is closely related to the cannabinoid receptor type 1, which is largely responsible for the efficacy of endocannabinoid-mediated presynaptic-inhibition, the psychoactive properties of tetrahydrocannabinol, the active agent in cannabis, and other phytocannabinoids (plant cannabinoids). The principal endogenous ligand for the CB2 receptor is 2-arachidonoylglycerol (2-AG). The cannabinoid receptor type 2, abbreviated as CB2, is a G protein-coupled receptor from the cannabinoid receptor family that in humans is encoded by the CNR2 gene. It is closely related to the cannabinoid receptor type 1, which is largely responsible for the efficacy of endocannabinoid-mediated presynaptic-inhibition, the psychoactive properties of tetrahydrocannabinol, the active agent in cannabis, and other phytocannabinoids (plant cannabinoids). The principal endogenous ligand for the CB2 receptor is 2-arachidonoylglycerol (2-AG). CB2 was cloned in 1993 by a research group from Cambridge looking for a second cannabinoid receptor that could explain the pharmacological properties of tetrahydrocannabinol. The receptor was identified among cDNAs based on its similarity in amino-acid sequence to the cannabinoid receptor type 1 (CB1) receptor, discovered in 1990. The discovery of this receptor helped provide a molecular explanation for the established effects of cannabinoids on the immune system. 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. As is commonly seen in G protein-coupled receptors, the CB2 receptor has seven transmembrane spanning domains, a glycosylated N-terminus, and an intracellular C-terminus. The C-terminus of CB2 receptors appears to play a critical role in the regulation of ligand-induced receptor desensitization and downregulation following repeated agonist application, perhaps causing the receptor to become less responsive to particular ligands. The human CB1 and the CB2 receptors possess approximately 44% amino acid similarity. When only the transmembrane regions of the receptors are considered, however, the amino acid similarity between the two receptor subtypes is approximately 68%. The amino acid sequence of the CB2 receptor is less highly conserved across human and rodent species as compared to the amino acid sequence of the CB1 receptor. 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. Like the CB1 receptors, CB2 receptors inhibit the activity of adenylyl cyclase through their Gi/Goα subunits. 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 critically regulates a number of important cellular processes in both 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 as well as in an induction of the growth-related gene Zif268 (also known as Krox-24, NGFI-A, and egr-1). The Zifi268 gene encodes a transcriptional regulator implicated in neuroplasticity and long term memory formation. At present, there are five recognized cannabinoids produced endogenously throughout the body: Arachidonoylethanolamine (anandamide), 2-arachidonoyl glycerol (2-AG), 2-arachidonyl glyceryl ether (noladin ether), virodhamine, as well as the recently discovered N-arachidonoyl-dopamine (NADA). Many of these ligands appear to exhibit properties of functional selectivity at the CB2 receptor: 2-AG preferentially activates the MAPK-ERK pathway, while noladin preferentially inhibits adenylyl cyclase. Like noladin, the synthetic ligand CP-55,940 has also been shown to preferentially inhibit adenylyl cyclase in CB2 receptors. Together, these results support the emerging concept of agonist-directed trafficking at the cannabinoid receptors. 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 the Central Nervous System expression of the CB2 receptor. 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. Initial investigation of CB2 receptor expression patterns focused on the presence of CB2 receptors in the peripheral tissues of the immune system and found CB2 receptor mRNA is found throughout tissues of the spleen, tonsils, and thymus gland. Northern blot analysis further indicates the expression of the CNR2 gene in immune tissues, where they are primarily responsible for mediating cytokine release. These receptors were primarily localized on immune cells such as monocytes, macrophages, B-cells, and T-cells.