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Molecular Pharmacology

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Research ArticleArticle

Diacylglycerol Lipase-α and -β Control Neurite Outgrowth in Neuro-2a Cells through Distinct Molecular Mechanisms

Kwang-Mook Jung, Giuseppe Astarita, Dean Thongkham and Daniele Piomelli
Molecular Pharmacology July 2011, 80 (1) 60-67; DOI: https://doi.org/10.1124/mol.110.070458
Kwang-Mook Jung
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Giuseppe Astarita
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Dean Thongkham
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Daniele Piomelli
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Abstract

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.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • This work was supported by the National Institutes of Health National Institute on Drug Abuse [Grant R01-DA012447].

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.110.070458.

  • ABBREVIATIONS:

    2-AG
    2-arachidonoyl-sn-glycerol
    ABHD
    α-β-hydrolase domain
    CB
    cannabinoid
    DAG
    1,2-diacyl-sn-glycerol
    DGL
    1,2-diacyl-sn-glycerol lipase
    GFP
    green fluorescent protein
    DHPG
    (S)-3,5-dihydroxyphenylglycine
    EGFP
    enhanced green fluorescent protein
    MAG
    monoacylglycerol
    mGlu
    metabotropic glutamate
    PCR
    polymerase chain reaction
    PLC
    phospholipase C
    RA
    all-trans-retinoic acid
    shRNA
    short hairpin RNA
    DAPI
    4,6-diamidino-2-phenylindole
    RNAi
    RNA interference
    JZL184
    4-nitrophenyl-4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate
    WWL70
    N-methyl-N-[[3-(4-pyridinyl)phenyl]methyl]-4′-(aminocarbonyl)[1,1′-biphenyl]-4-yl ester, carbamic acid
    SR141716A
    rimonabant, N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride.

  • Received December 9, 2010.
  • Accepted April 13, 2011.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 80 (1)
Molecular Pharmacology
Vol. 80, Issue 1
1 Jul 2011
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Research ArticleArticle

Diacylglycerol Lipase-α and -β Control Neurite Outgrowth in Neuro-2a Cells through Distinct Molecular Mechanisms

Kwang-Mook Jung, Giuseppe Astarita, Dean Thongkham and Daniele Piomelli
Molecular Pharmacology July 1, 2011, 80 (1) 60-67; DOI: https://doi.org/10.1124/mol.110.070458

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Research ArticleArticle

Diacylglycerol Lipase-α and -β Control Neurite Outgrowth in Neuro-2a Cells through Distinct Molecular Mechanisms

Kwang-Mook Jung, Giuseppe Astarita, Dean Thongkham and Daniele Piomelli
Molecular Pharmacology July 1, 2011, 80 (1) 60-67; DOI: https://doi.org/10.1124/mol.110.070458
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