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Volume 17, Number 4,
Issue of February 15, 1997
pp. 1226-1242
Copyright ©1997 Society for Neuroscience
Occurrence and Biosynthesis of Endogenous Cannabinoid Precursor,
N-Arachidonoyl Phosphatidylethanolamine, in Rat
Brain
Received Oct. 4, 1996; revised Nov. 18, 1996; accepted Nov. 25, 1996.
Hugues Cadas,
Emmanuelle di
Tomaso, and
Daniele Piomelli
The Neurosciences Institute, San Diego, California 92121
It has been suggested that anandamide
(N-arachidonoylethanolamine), an endogenous
cannabinoid substance, may be produced through Ca2+-stimulated hydrolysis of the phosphatidylethanolamine
(PE) derivative N-arachidonoyl PE. The presence
of N-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) and N-arachidonoyl PE (22 ± 16 pmol/gm), as assessed
by gas chromatography/mass spectrometry. We describe a
N-acyltransferase activity in brain that catalyzes the
biosynthesis of N-arachidonoyl PE by transferring an
arachidonate group from the sn-1 carbon of phospholipids
to the amino group of PE. We also show that sn-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 of
N-acyltransferase activity in primary cultures of cortical neurons prevents Ca2+-stimulated
N-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 precursor N-arachidonoyl PE. They also
suggest that biosynthesis of N-arachidonoyl PE and
formation of anandamide are tightly coupled processes, which may
concomitantly be stimulated by elevations in intracellular
Ca2+ occurring during neural activity.
Key words:
anandamide;
N-acylethanolamines;
phosphatidylethanolamine;
N-acylphosphatidylethanolamine;
N-acyltransferase;
arachidonate;
endogenous cannabinoids
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