The serine hydrolases MAGL, ABHD6 and ABHD12 as guardians of 2-arachidonoylglycerol signalling through cannabinoid receptors

The endocannabinoid 2‐arachidonoylglycerol (2‐AG) is a lipid mediator involved in various physiological processes. In response to neural activity, 2‐AG is synthesized post‐synaptically, then activates pre‐synaptic cannabinoid CB1 receptors (CB1Rs) in a retrograde manner, resulting in transient and long‐lasting reduction of neurotransmitter release. The signalling competence of 2‐AG is tightly regulated by the balanced action between ‘on demand’ biosynthesis and degradation. We review recent research on monoacylglycerol lipase (MAGL), ABHD6 and ABHD12, three serine hydrolases that together account for approx. 99% of brain 2‐AG hydrolase activity. MAGL is responsible for approx. 85% of 2‐AG hydrolysis and colocalizes with CB1R in axon terminals. It is therefore ideally positioned to terminate 2‐AG‐CB1R signalling regardless of the source of this endocannabinoid. Its acute pharmacological inhibition leads to 2‐AG accumulation and CB1R‐mediated behavioural responses. Chronic MAGL inactivation results in 2‐AG overload, desensitization of CB1R signalling and behavioural tolerance. ABHD6 accounts for approx. 4% of brain 2‐AG hydrolase activity but in neurones it rivals MAGL in efficacy. Neuronal ABHD6 resides post‐synaptically, often juxtaposed with CB1Rs, and its acute inhibition leads to activity‐dependent accumulation of 2‐AG. In cortical slices, selective ABHD6 blockade facilitates CB1R‐dependent long‐term synaptic depression. ABHD6 is therefore positioned to guard intracellular pools of 2‐AG at the site of generation. ABHD12 is highly expressed in microglia and accounts for approx. 9% of total brain 2‐AG hydrolysis. Mutations in ABHD12 gene are causally linked to a neurodegenerative disease called PHARC. Whether ABHD12 qualifies as a bona fide member to the endocannabinoid system remains to be established.