BIOSYNTHESIS OF AN ENDOGENOUS CANNABINOID PRECURSOR IN NEURONS AND ITS CONTROL BY CALCIUM AND CAMP

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.