PDF(Pubmed)
Abstract：
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.
摘要：
2-花生四酰基甘油（2-AG）是最丰富的内源性大麻素（EC），作为CB1和CB2大麻素受体的完全激动剂。通过磷酸肌醇特异性磷脂酶Cβ1（PLCβ1）和二酰基甘油脂肪酶α（DAGLα）的顺序作用，在突触后膜中按需合成，与突触前CB1相互作用时有助于逆行信号传导。然而,2-AG生产还可能涉及PLC和DAGL同工型的各种组合，以及暗示其他酶和底物的其他细胞内途径。2-AG合成的其他三个替代途径取决于三种不同的水解酶对2-花生四酰基溶血磷脂的细胞外裂解：甘油磷酸二酯酶3（GDE3），脂质磷酸磷酸酶（LPP），和两个外核苷酸焦磷酸酶/磷酸二酯酶（ENPP6-7）成员。我们建议AlterAG-1，-2和-3的三个途径共享一个外细胞定位的名称，允许它们将细胞外溶血磷脂介质转化为2-AG，从而诱导各种G蛋白偶联受体（GPCRs）之间的典型信号转换。这意味着溶血磷脂（LPLs）和2-AG的区域异构现象至关重要，这是本综述深入分析的对象。AlterAG的确切功能作用仍然知之甚少，需要基因无效的方法，知道2-AG及其相关的溶血磷脂涉及许多生理和病理学方面，包括癌症,炎症,免疫防御,肥胖，骨发育，神经变性,或精神疾病。
