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 mol.110.070458
DO 10.1124/mol.110.070458
A1 Kwang-Mook Jung
A1 Giuseppe Astarita
A1 Dean Thongkham
A1 Daniele Piomelli
YR 2011
UL http://molpharm.aspetjournals.org/content/early/2011/04/14/mol.110.070458.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. Knock-down 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 peri-nuclear lipid droplets, whereas DGL-α is found on plasma membranes. Following RA-induced differentiation, both DGL-α- and DGL-β-GFP 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 CB1 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.