RT Journal Article SR Electronic T1 Diacylglycerol Lipase-α and -β Control Neurite Outgrowth in Neuro-2a Cells through Distinct Molecular Mechanisms JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 60 OP 67 DO 10.1124/mol.110.070458 VO 80 IS 1 A1 Kwang-Mook Jung A1 Giuseppe Astarita A1 Dean Thongkham A1 Daniele Piomelli YR 2011 UL http://molpharm.aspetjournals.org/content/80/1/60.abstract AB The endocannabinoid 2-arachidonoyl-sn-glycerol (2-AG) is produced through hydrolysis of 1,2-diacyl-sn-glycerol (DAG), which is catalyzed by DAG lipase (DGL). Two DGL isoforms have been molecularly cloned, but their respective roles in endocannabinoid signaling have not been fully elucidated. Here, we report that DGL-α and DGL-β may contribute to all-trans-retinoic acid (RA)-induced neurite outgrowth in neuroblastoma Neuro-2a cells through distinct mechanisms. RA-induced differentiation of Neuro-2a cells was associated with elevations of cellular 2-AG levels and DGL activity, which were accompanied by temporally separated transcription of DGL-α and DGL-β mRNA. Knockdown of either DGL-α or DGL-β expression attenuated neurite outgrowth, which indicates that both isoforms contribute to neuritogenesis. Immunostaining experiments showed that DGL-β is localized to perinuclear lipid droplets, whereas DGL-α is found on plasma membranes. After RA-induced differentiation, both DGL-α- and DGL-β-green fluorescent protein were distributed also in neurites but in distinguishable patterns. Overexpression of either DGL-α or DGL-β increased the number of neurite-bearing cells, but DGL-β caused substantially larger morphological changes than DGL-α did. Finally, the cannabinoid-1 antagonist rimonabant (1 μM) inhibited DGL-α-induced neuritogenesis, whereas it had no such effect on DGL-β-induced morphological differentiation. The results indicate that RA-induced DGL expression is required for neurite outgrowth of Neuro-2a cells. The findings further suggest that DGL-α and -β may regulate neurite outgrowth by engaging temporally and spatially distinct molecular pathways.