2-AG is a monoacylglycerol synthesised on demand from membrane phospholipids, primarily via the enzyme diacylglycerol lipase (DAGLα/β). Unlike classical neurotransmitters, it is not stored in vesicles; it is produced post-synaptically and travels retrogradely across the synapse to activate presynaptic CB1 receptors. This retrograde signalling mechanism underpins 2-AG's recognised role in modulating neurotransmitter release, a process described in the literature as depolarisation-induced suppression of inhibition (DSI) and depolarisation-induced suppression of excitation (DSE).
Structurally, 2-AG is an ester of arachidonic acid and glycerol. Its primary degradation pathway is hydrolysis by monoacylglycerol lipase (MAGL), which yields arachidonic acid and glycerol as metabolites. Cyclooxygenase-2 (COX-2) can also oxidise 2-AG, producing prostaglandin-glycerol esters whose physiological significance continues to be investigated. Circulating 2-AG concentrations in human plasma are typically reported in the low nanomolar range, substantially higher than those of the related endocannabinoid anandamide (AEA).
2-AG is a full agonist at both CB1 and CB2 receptors, in contrast to anandamide, which behaves as a partial agonist at CB1. CB2 receptors are expressed predominantly on immune-lineage cells, and 2-AG is therefore studied in the context of peripheral immune signalling as well as central nervous system physiology. It also acts at the transient receptor potential vanilloid 1 (TRPV1) channel and certain peroxisome proliferator-activated receptors (PPARs), though the functional relevance of these interactions at physiological concentrations remains an active area of enquiry.
Note on deficiency hypotheses: Some researchers have proposed that chronically reduced endocannabinoid tone , including low 2-AG availability , may be associated with certain physiological states. These proposals remain hypotheses only; causal relationships in humans have not been established and no diagnostic test for "endocannabinoid deficiency" is currently validated or approved by the Therapeutic Goods Administration (TGA).
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