Involvement of the γ Isoform of cPLA in the Biosynthesis of Bioactive Acylethanolamines.

Arachidonylethanolamide (anandamide) acts as an endogenous ligand of cannabinoid receptors, while other acylethanolamines (NAEs), such as palmitylethanolamide and oleylethanolamide, show analgesic, anti-inflammatory, and appetite-suppressing effects through other receptors. In mammalian tissues, NAEs, including anandamide, are produced from glycerophospholipid via acyl-phosphatidylethanolamine (NAPE). The ɛ isoform of cytosolic phospholipase A (cPLA) functions as an acyltransferase to form NAPE. Since the cPLA family consists of six isoforms (α, β, γ, δ, ɛ, and ζ), the present study investigated a possible involvement of isoforms other than ɛ in the NAE biosynthesis. Firstly, when the cells overexpressing one of the cPLA isoforms were labeled with [C]ethanolamine, the increase in the production of [C]NAPE was observed only with the ɛ-expressing cells. Secondly, when the cells co-expressing ɛ and one of the other isoforms were analyzed, the increase in [C]-acyl-lysophosphatidylethanolamine (lysoNAPE) and [C]NAE was seen with the combination of ɛ and γ isoforms. Furthermore, the purified cPLAγ hydrolyzed not only NAPE to lysoNAPE, but also lysoNAPE to glycerophospho--acylethanolamine (GP-NAE). Thus, the produced GP-NAE was further hydrolyzed to NAE by glycerophosphodiesterase 1. These results suggested that cPLAγ is involved in the biosynthesis of NAE by its phospholipase A/A and lysophospholipase activities.