Devane WA; Axelrod J
Enzymatic synthesis of anandamide, an endogenous ligand for the
cannabinoid receptor, by brain membranes.
Laboratory of Cell Biology, National Institute of Mental Health, Bethesda,
MD 20892.
Source: Proc Natl Acad Sci U S A 1994 Jul
5;91(14):6698-701
Unique Identifier: 94294446
Abstract:
Anandamide, an endogenous eicosanoid derivative (arachidonoylethanolamide),
binds to the cannabinoid receptor, a member of the G protein-coupled
superfamily. It also inhibits both adenylate cyclase and N-type calcium
channel opening. The enzymatic synthesis of anandamide in bovine brain
tissue was examined by incubating brain membranes with [14C]ethanolamine
and arachidonic acid. Following incubation and extraction into toluene, a
radioactive product was identified which had the same Rf value as authentic
anandamide in several thin-layer chromatographic systems. When structurally
similar fatty acid substrates were compared, arachidonic acid exhibited the
lowest EC50 and the highest activity for enzymatic formation of the
corresponding ethanolamides. The concentration-response curve of
arachidonic acid exhibited a steep slope, and at higher concentrations
arachidonate inhibited enzymatic activity. When brain homogenates were
separated into subcellular fractions by sucrose density gradient
centrifugation, anandamide synthase activity was highest in fractions
enriched in synaptic vesicles, myelin, and microsomal and synaptosomal
membranes. When several areas of brain were examined, anandamide synthase
activity was found to be highest in the hippocampus, followed by the
thalamus, cortex, and striatum, and lowest in the cerebellum, pons, and
medulla. The ability of brain tissue to enzymatically synthesize anandamide
and the existence of specific receptors for this eicosanoid suggest the
presence of anandamide-containing (anandaergic) neurons.
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