2arakidonoylglyceroli

2-arachidonoylglycerol (2-AG) is an endogenous lipid signaling molecule and one of the principal endocannabinoids of the mammalian nervous system. It is a monoacylglycerol formed by the esterification of arachidonic acid to glycerol at the sn-2 position, making it a high-affinity ligand for cannabinoid receptors. Along with anandamide (AEA), 2-AG is a central mediator of the endocannabinoid system.

Biosynthesis and inactivation: 2-AG is produced on demand in many cells, particularly neurons. In the postsynaptic neuron, signaling can activate phospholipase C to generate diacylglycerol (DAG), which is then hydrolyzed by diacylglycerol lipase to yield 2-AG. 2-AG acts as a retrograde messenger, activating presynaptic CB1 receptors to modulate neurotransmitter release. Termination of 2-AG signaling occurs mainly through hydrolysis by monoacylglycerol lipase (MGL) to arachidonic acid and glycerol, with additional contributions from enzymes such as ABHD6 and ABHD12 and by re-esterification pathways.

Receptors and signaling: 2-AG is a full agonist at both CB1 and CB2 receptors, with particularly high CB1 activity in the brain. Through CB1/CB2 signaling, it regulates synaptic transmission and plasticity, contributing to processes such as depolarization-induced suppression of inhibition and excitation (DSI/DSE). Under certain conditions, 2-AG can be metabolized by COX-2 to prostaglandin glycerol esters, and there is evidence of activity at other targets at lower potency.

Physiological relevance: Endogenously produced 2-AG is found in brain and peripheral tissues at micromolar levels and participates in pain modulation, appetite, mood, and neuroprotection. It is a focus of research on pain, metabolic disorders, and neurodegenerative diseases, and is commonly measured in lipidomics studies.