| Cannabinoid receptor 2 (CB2), encoded by the CNR2 gene, is a class A G protein–coupled receptor of the endocannabinoid system that is preferentially expressed in immune and hematopoietic lineages and functions as a key regulator of inflammatory and immune responses. The receptor adopts the typical seven–transmembrane helical architecture of rhodopsin-like GPCRs and couples predominantly to Gi/o proteins, which link ligand binding to inhibition of adenylyl cyclase, reduced cAMP levels, and modulation of ion channels and downstream kinase cascades. Endogenous ligands such as 2-arachidonoylglycerol and anandamide, as well as plant-derived and synthetic cannabinoids, activate CB2 to trigger Gi/o-dependent signaling that decreases cAMP production, alters protein kinase A activity, and influences MAPK pathways including ERK, p38, and JNK, thereby shaping transcriptional outputs that control cytokine expression, cell survival, and differentiation programs in immune cells. CB2 is abundant in spleen, tonsil, and other secondary lymphoid organs, and is highly expressed on B cells, natural killer cells, monocytes, macrophages, and microglia, where its activation limits cell migration, reduces the release of pro-inflammatory mediators, and promotes a shift toward anti-inflammatory or resolution-phase phenotypes, positioning CB2 as a brake on excessive immune activation. In the nervous system, CB2 expression is prominent on microglia and other glial elements and is induced under injury and neuroinflammatory conditions; activation at these sites modulates microglial activation state, influences neuroimmune cross-talk, and contributes to neuroprotective mechanisms in models of neuropathic pain and neurodegeneration. Signal transduction downstream of CB2 extends to regulation of chemokine receptor signaling, leukocyte trafficking, and osteoclast and osteoblast activity, linking this receptor to bone remodeling, atherosclerosis, and other chronic inflammatory pathologies in which endocannabinoid tone and CB2 responsiveness affect disease course. CB2 is only sparsely expressed in most neurons under basal conditions and lacks the strong association with psychotropic effects seen for CB1, which makes CB2 an attractive pharmacological target to modulate pain, inflammation, fibrosis, and neurodegeneration with reduced central side effects. |
