The endocannabinoid system comprises two GPCR receptors, CNR1 and CNR2, their endogenous ligands, the endocannabinoids, and the enzymes that regulate endocannabinoid biosynthesis, degradation, and tissue levels. CNR1 receptors are expressed at high levels in the central nervous system, whereas CNR2 receptors are concentrated predominantly, although not exclusively, in cells of the immune system. CNR2 expression is also detected in the brainstem, cortex and cerebellar neurons and microglia.Endocannabinoids are endogenous lipid-signaling molecules that are generated in the cell membrane from phospholipid precursors. The two best characterized endocannabinoids are anandamide (AEA) and 2-arachidonoylglycerol (2-AG). AEA is an unsaturated fatty acid derivative belonging to the N-acylethanolamide group and it is hydrolyzed to arachidonic acid and ethanolamine by an intracellular fatty acid amide hydrolase (FAAH). 2-AG is hydrolyzed mainly by monoacylglycerol lipase (MAGL/MGLL).
Endocannabinoids have been identified as neurodevelopmental signaling cues that have a regulatory role on the molecular and cellular mechanisms involved in brain development. The CNRs in concert with locally produced endocannabinoids regulate neural progenitor proliferation, pyramidal specification and axonal navigation.
CNR receptor-mediated proliferative and pro-survival actions have been attributed, at least in part, to the activation of the PI3K/Akt axis and ERK/mTORC1 pathway. PI3K/Akt pathway influences the activity of the transcriptional regulators Pax6 and CREB and their control of neural progenitor proliferation and fate decisions. A downstream target of activated Akt is the cytoplasmic BRCA1, which is referred to as one of the candidate E3 ubiquitin ligases controlling MAGL degradation.
Furthermore, activation of the CNR1 /Gαi/o leads to the activation of a cascade of signaling components, including Rap1, Ral, Src, Rac, and JNK, resulting in both Tyr and Ser phosphorylation of Stat3, which have critical role in neurite outgrowth. CNRs activation can also modulate the activity of RhoA to induce growth cone repulsion and collapse in GABAergic interneuron.