Parsing the players: 2‐arachidonoylglycerol synthesis and degradation in the CNS

The endogenous cannabinoid signalling system, composed of endogenous cannabinoids, cannabinoid receptors and the enzymes that synthesize and degrade the endogenous cannabinoids, is much more complex than initially conceptualized. 2‐Arachidonoylglycerol (2‐AG) is the most abundant endocannabinoid and plays a major role in CNS development and synaptic plasticity. Over the past decade, many key players in 2‐AG synthesis and degradation have been identified and characterized. Most 2‐AG is synthesized from membrane phospholipids via sequential activation of a phospholipase Cβ and a diacylglycerol lipase, although other pathways may contribute in specialized settings. 2‐AG breakdown is more complicated with at least eight different enzymes participating. These enzymes can either degrade 2‐AG into its components, arachidonic acid and glycerol, or transform 2‐AG into highly bioactive signal molecules. The implications of the precise temporal and spatial control of the expression and function of these pleiotropic metabolizing enzymes have only recently come to be appreciated. In this review, we will focus on the primary organization of the synthetic and degradative pathways of 2‐AG and then discuss more recent findings and their implications, with an eye towards the biological and therapeutic implications of manipulating 2‐AG synthesis and metabolism.