From Classical to Alternative Pathways of 2-Arachidonoylglycerol Synthesis: AlterAGs at the Crossroad of Endocannabinoid and Lysophospholipid Signaling

• Published in: Molecules (Basel, Switzerland) Vol. 29; no. 15; p. 3694
• Main Authors: Briand-Mésange, Fabienne, Gennero, Isabelle, Salles, Juliette, Trudel, Stéphanie, Dahan, Lionel, Ausseil, Jérôme, Payrastre, Bernard, Salles, Jean-Pierre, Chap, Hugues
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.08.2024
• Subjects: 2-arachidonoylglycerol; Acids; Animals; Arachidonic Acids - metabolism; Body fat; Brain-derived neurotrophic factor; Dopamine; endocannabinoids; Endocannabinoids - metabolism; Enzymes; Glycerides - metabolism; Glycerol; Humans; Kinases; Lipase; lysophosphatidic acid; lysophosphatidylcholine; lysophosphatidylinositol; lysophosphatidylserine; Lysophospholipids - metabolism; Metabolism; Nervous system; Phosphatases; Phosphoric Diester Hydrolases - metabolism; Physiological aspects; Physiology; Plasma; Proteins; Signal Transduction; France; lysophosphatidylserine; plasticity-related-gene 1; lysophosphatidylcholine; lysophosphatidic acid; autotaxin; lipid phosphate phosphatases; ENPP; GDE3; endocannabinoids; 2-arachidonoylglycerol; lysophosphatidylinositol
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules29153694

2-arachidonoylglycerol (2-AG) is the most abundant endocannabinoid (EC), acting as a full agonist at both CB1 and CB2 cannabinoid receptors. It is synthesized on demand in postsynaptic membranes through the sequential action of phosphoinositide-specific phospholipase Cβ1 (PLCβ1) and diacylglycerol lipase α (DAGLα), contributing to retrograde signaling upon interaction with presynaptic CB1. However, 2-AG production might also involve various combinations of PLC and DAGL isoforms, as well as additional intracellular pathways implying other enzymes and substrates. Three other alternative pathways of 2-AG synthesis rest on the extracellular cleavage of 2-arachidonoyl-lysophospholipids by three different hydrolases: glycerophosphodiesterase 3 (GDE3), lipid phosphate phosphatases (LPPs), and two members of ecto-nucleotide pyrophosphatase/phosphodiesterases (ENPP6-7). We propose the names of AlterAG-1, -2, and -3 for three pathways sharing an ectocellular localization, allowing them to convert extracellular lysophospholipid mediators into 2-AG, thus inducing typical signaling switches between various G-protein-coupled receptors (GPCRs). This implies the critical importance of the regioisomerism of both lysophospholipid (LPLs) and 2-AG, which is the object of deep analysis within this review. The precise functional roles of AlterAGs are still poorly understood and will require gene invalidation approaches, knowing that both 2-AG and its related lysophospholipids are involved in numerous aspects of physiology and pathology, including cancer, inflammation, immune defenses, obesity, bone development, neurodegeneration, or psychiatric disorders.