Peroxide-Dependent MGL Sulfenylation Regulates 2-AG-Mediated Endocannabinoid Signaling in Brain Neurons

• The second messenger hydrogen peroxide inhibits monoacylglycerol lipase (MGL)
• Hydrogen peroxide sulfenylates cysteines C201 and C208 in MGL
• MGL sulfenylation elevates 2-AG-mediated endocannabinoid signaling in neurons
• MGL sulfenylation may serve a presynaptic control point for endocannabinoid signaling

SummaryThe second messenger hydrogen peroxide transduces changes in the cellular redox state by reversibly oxidizing protein cysteine residues to sulfenic acid. This signaling event regulates many cellular processes but has never been shown to occur in the brain. Here, we report that hydrogen peroxide heightens endocannabinoid signaling in brain neurons through sulfenylation of cysteines C201 and C208 in monoacylglycerol lipase (MGL), a serine hydrolase that deactivates the endocannabinoid 2-arachidonoyl-sn-glycerol (2-AG) in nerve terminals. The results suggest that MGL sulfenylation may provide a presynaptic control point for 2-AG-mediated endocannabinoid signaling.

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