Occurrence and Biosynthesis of Endogenous Cannabinoid Precursor,N-Arachidonoyl Phosphatidylethanolamine, in Rat Brain

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Abstract
It has been suggested that anandamide (N-arachidonoylethanolamine), an endogenous cannabinoid substance, may be produced through Ca2+-stimulated hydrolysis of the phosphatidylethanolamine (PE) derivativeN-arachidonoyl PE. The presence ofN-arachidonoyl PE in adult brain tissue and the enzyme pathways that underlie its biosynthesis are, however, still undetermined. We report here that rat brain tissue contains both anandamide (11 ± 7 pmol/gm wet tissue) andN-arachidonoyl PE (22 ± 16 pmol/gm), as assessed by gas chromatography/mass spectrometry. We describe aN-acyltransferase activity in brain that catalyzes the biosynthesis ofN-arachidonoyl PE by transferring an arachidonate group from thesn-1 carbon of phospholipids to the amino group of PE. We also show thatsn-1 arachidonoyl phospholipids are present in brain, where they constitute ∼0.5% of total phospholipids.N-acyltransferase activity is Ca2+dependent and is enriched in brain and testis. Within the brain,N-acyltransferase activity is highest in brainstem; intermediate in cortex, striatum, hippocampus, medulla, and cerebellum; and lowest in thalamus, hypothalamus, and olfactory bulb. Pharmacological inhibition ofN-acyltransferase activity in primary cultures of cortical neurons prevents Ca2+-stimulatedN-arachidonoyl PE biosynthesis. Our results demonstrate, therefore, that rat brain tissue contains the complement of enzymatic activity and lipid substrates necessary for the biosynthesis of the anandamide precursorN-arachidonoyl PE. They also suggest that biosynthesis ofN-arachidonoyl PE and formation of anandamide are tightly coupled processes, which may concomitantly be stimulated by elevations in intracellular Ca2+occurring during neural activity.

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