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Volume 16, Number 12, Issue of June 15, 1996 pp. 3934-3942
Copyright ©1996 Society for Neuroscience

Biosynthesis of an Endogenous Cannabinoid Precursor in Neurons and its Control by Calcium and cAMP

Received Feb. 14, 1996; revised March 27, 1996; accepted April 1, 1996.

Hugues Cadas1, Sylvie Gaillet2, Massimiliano Beltramo1, Laurent Venance2, and Daniele Piomelli1

1 The Neurosciences Institute, San Diego, California 92121, and 2 Institut National de la Santé et de la Recherche Médicale, Paris, France

Understanding the mechanisms involved in the biogenesis of N-arachidonoylethanolamine (anandamide) and Npalmitoylethanolamine is important in view of the possible role of these lipids as endogenous cannabinoid substances. Anandamide (which activates cannabinoid CB1 receptors) and N-palmitoylethanolamine (which activates a CB2-like receptor subtype in mast cells) may both derive from cleavage of precursor phospholipid, N-acylphosphatidylethanolamine (NAPE), catalyzed by Ca2+-activated D-type phosphodiesterase activity. We report here that the de novo biosynthesis of NAPE is enhanced in a Ca2+-dependent manner when rat cortical neurons are stimulated with the Ca2+-ionophore ionomycin or with membrane-depolarizing agents such as veratridine and kainate. This reaction is likely to be mediated by a neuronal N-acyltransferase activity, which catalyzes the transfer of an acyl group from phosphatidylcholine to the ethanolamine moiety of phosphatidylethanolamine. In addition, we show that Ca2+-dependent NAPE biosynthesis is potentiated by agents that increase cAMP levels, including forskolin and vasoactive intestinal 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-acylethanolamines during synaptic activity, and prime target neurons for release of these bioactive lipids.

Key words: anandamide; N-acylethanolamines; phosphatidylethanolamine; N-acylphosphatidylethanolamine; N-acyltransferase; vasoactive intestinal peptide; endogenous cannabinoids




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