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Inactivation of N-Acyl Phosphatidylethanolamine Phospholipase D Reveals Multiple Mechanisms for the Biosynthesis of Endocannabinoids

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    Inactivation of N-Acyl Phosphatidylethanolamine Phospholipase D Reveals Multiple Mechanisms for the Biosynthesis of Endocannabinoids†
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    The Skaggs Institute for Chemical Biology and Departments of Cell Biology and Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037
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    Biochemistry

    Cite this: Biochemistry 2006, 45, 15, 4720–4726
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    https://doi.org/10.1021/bi060163l
    Published March 23, 2006
    Copyright © 2006 American Chemical Society
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    Abstract

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    N-Acyl ethanolamines (NAEs) constitute a large and diverse class of signaling lipids that includes the endogenous cannabinoid anandamide. Like other lipid transmitters, NAEs are thought to be biosynthesized and degraded on-demand rather than being stored in vesicles prior to signaling. The identification of enzymes involved in NAE metabolism is therefore imperative to achieve a complete understanding of this lipid signaling system and control it for potential therapeutic gain. Recently, an N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD) was identified as a candidate enzyme involved in the biosynthesis of NAEs. Here, we describe the generation and characterization of mice with a targeted disruption in the NAPE-PLD gene [NAPE-PLD(−/−) mice]. Brain tissue from NAPE-PLD(−/−) mice showed more than a 5-fold reduction in the calcium-dependent conversion of NAPEs to NAEs bearing both saturated and polyunsaturated N-acyl chains. However, only the former group of NAEs was decreased in level in NAPE-PLD(−/−) brains, and these reductions were most dramatic for NAEs bearing very long acyl chains (≥C20). Further studies identified a calcium-independent PLD activity in brains from NAPE-PLD(−/−) mice that accepted multiple NAPEs as substrates, including the anandamide precursor C20:4 NAPE. The illumination of distinct enzymatic pathways for the biosynthesis of long chain saturated and polyunsaturated NAEs suggests a strategy to control the activity of specific subsets of these lipids without globally affecting the function of the NAE family as a whole.

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    †

     This work was supported by the National Institutes of Health (DA015197 and DA017259), the Helen L. Dorris Child and Adolescent Neuro-Psychiatric Disorder Institute, and the Skaggs Institute for Chemical Biology. D.L. is supported by a NARSAD Young Investigator Fellowship. A.S. is supported by a Merck Fellowship of the Life Science Research Foundation and a Burroughs Wellcome Fund Career Award.

    ‡

     These authors contributed equally to this work.

    *

     To whom correspondence should be addressed. Tel:  858-784-8633. Fax:  858-784-8023. E-mail:  [email protected].

    Supporting Information Available

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    Expanded methods section, a table showing elevated NAE levels in FAAH(−/−) mice, and two figures showing equivalent FAAH expression in NAPE-PLD(+/+) and -(−/−) mice and equivalent anandamide levels in NAPE-PLD(−/−) mice treated with the FAAH inhibitor URB597. This material is available free of charge via the Internet at http://pubs.acs.org.

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    Biochemistry

    Cite this: Biochemistry 2006, 45, 15, 4720–4726
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    https://doi.org/10.1021/bi060163l
    Published March 23, 2006
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