Cannabinoid receptor 2

The cannabinoid receptor 2 (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 1 (CB1), which is largely responsible for the efficacy of endocannabinoid-mediated presynaptic-inhibition, the psychoactive properties of tetrahydrocannabinol (THC), 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 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/Go_α subunits. CB2 can also couple to stimulatory Gα_s subunits leading to an increase of intracellular cAMP, as has been shown for human leukocytes. Through their G_βγ 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 G_βγ 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, as well as N-arachidonoyl-dopamine (NADA). 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.

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.