H. Cadas et al., BIOSYNTHESIS OF AN ENDOGENOUS CANNABINOID PRECURSOR IN NEURONS AND ITS CONTROL BY CALCIUM AND CAMP, The Journal of neuroscience, 16(12), 1996, pp. 3934-3942
Understanding the mechanisms involved in the biogenesis of N-arachidon
oylethanolamine (anandamide) and N-palmitoylethanolamine is important
in view of the possible role of these lipids as endogenous cannabinoid
substances, Anandamide (which activates cannabinoid CB1 receptors) an
d N-palmitoylethanolamine (which activates a CB2-like receptor subtype
in mast cells) may both derive from cleavage of precursor phospholipi
d, N-acylphosphatidylethanolamine (NAPE), catalyzed by Ca2+-activated
D-type phosphodiesterase activity. We report here that the de novo bio
synthesis of NAPE is enhanced in a Ca2+-dependent manner when rat cort
ical neurons are stimulated with the Ca2+-ionophore ionomycin or with
membrane-depolarizing agents such as veratridine and kainate. This rea
ction is likely to be mediated by a neuronal N-acyltransferase activit
y, which catalyzes the transfer of an acyl group from phosphatidylchol
ine to the ethanolamine moiety of phosphatidylethanolamine. In additio
n, we show that Ca2+-dependent NAPE biosynthesis is potentiated by age
nts that increase cAMP levels, including forskolin and vasoactive inte
stinal peptide. Our results thus indicate that NAPE levels in cortical
neurons are controlled by Ca2+ ions and cAMP. Such regulatory effect
may participate in maintaining a supply of cannabimimetic N-acylethano
lamines during synaptic activity, and prime target neurons for release
of these bioactive lipids.