fig1

Figure 1. DAGLB and eCB signaling in DANs. (A) The cartoon illustrates the 3D protein structure of DAGLB predicted by AlphaFold; (B) DAGLB is suggested to be the main synthase of the eCB 2-AG in DANs^[27]. The 2-AG produced in the postsynaptic DANs by DAGLB and DAGLA are released into the synaptic cleft upon neuronal activation. They then retrogradely bind to CB1R in the presynaptic sites of DRD1-expressing dSPNs, leading to the suppression of neurotransmitter GABA release. GABA suppresses the activity of DANs and DA release. MGLL, associated with the presynaptic sites, mediates the degradation of 2-AG into AA and glycerol, thereby terminating the 2-AG-mediated presynaptic inhibition; (C) The loss-of-function variants in the DAGLB gene have been associated with early-onset recessive Parkinsonism, resulting in a reduction of 2-AG production from DANs, increased inhibitory inputs from dSPNs, and reduced dopamine release; (D) Augmentation of 2-AG levels in nigral regions, either through the supplementation of CB1R agonists or the inhibition of MGLL hydrolysis activity, could restore local 2-AG levels and dopamine transmission, offering a potential treatment avenue for the disease. DAGLB: Diacylglycerol lipase β; eCB: endocannabinoid; DANs: nigrostriatal dopaminergic neurons; 2-AG: 2-arachidonoyl-glycerol; DAGLA: diacylglycerol lipase α; CB1R: cannabinoid receptor 1; DRD1: dopamine receptor D1; dSPNs: direct pathway spiny projection neurons; GABA: gamma-aminobutyric acid; DA: dopamine; MGLL: monoacylglycerol lipase; AA: arachidonic acid.