Inactivation of N-acyl Phosphatidylethanolamine Phospholipase D Reveals Multiple Mechanisms for the Biosynthesis of Endocannabinoids.
From: The Skaggs Institute for Chemical Biology and Department of Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Biochemistry
- Publish Date: Apr 2006
- ISSN: 0006-2960
- Volume: 45
- Issue: 15
- Pages: 4720-6
- Medium: Print
- Language: English
- Citation (JAMA): Leung Donmienne, Saghatelian Alan, Simon Gabriel M, et al. Inactivation of N-acyl Phosphatidylethanolamine Phospholipase D Reveals Multiple Mechanisms for the Biosynthesis of Endocannabinoids.. Biochemistry Apr 2006;45:4720-6
Abstract
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 (>or=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.
Mesh Headings (Keywords): Animals, Brain, Endocannabinoids, Ethanolamines, Mice, Mice, Inbred C57BL, Models, Biological, Models, Genetic, Phosphatidylethanolamines, Phospholipase D, Recombinant Fusion Proteins, Signal Transduction
Check for Full Text / PubMed Unique Identifier (PMID): 16605240
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