What is Monoacylglycerol Lipase (MAGL)

Monoacylglycerol lipase, in the context of the endocannabinoid system (ECS), refers to the several enzymes responsible for degrading the endocannabinoid 2-arachidonoyl glycerol, or 2-AG.^1.

The name monoacylglycerol lipase says a lot about the function of the enzyme:

A fat, more correctly known as an acylglycerol, is any molecule that consists of one to three fatty acid chains bonded to a single glycerol molecule.

Monoacylglycerols (also: monoglycerides) are fats consisting of a single fatty acid chain, and glycerol.

A lipase is any enzyme that degrades a fat into its constituent fatty acid group(s) and glycerol, along with one molecule of water.

Therefore, a monoacylglycerol lipase is an enzyme that breaks the ester bond of a monoglyceride, such as 2-arachidonoyl glycerol (2-AG), producing one fatty acid molecule, one glycerol molecule, and one water molecule .

2-AG, which consists of a glycerol bonded to the fatty acid arachidonic acid (AA), is a monoglyceride. 2-AG is also the most potent endogenous agonist of both CB1 and CB2 cannabinoid receptors, so the role of MAGL in the degradation of 2-AG regulates much of the overall activity of the ECS.^{2, 3, 4.}

There are three distinct monoacylglycerol lipases present in the endocannabinoid system of the brain that are responsible for regulating the 2-AG concentrations across various brain regions. These include the archetypal MAGL, encoded by the MGLL gene, which is responsible for about 85% of all breakdown of 2-AG. MAGL is expressed by most brain regions and resides in the neuronal cytosol, with pseudo-membrane association.^5.

In addition, α/β hydrolase domain-containing 6 (ABHD6) and ABHD12 are two other types of monoacylglycerol lipase, responsible for 4% and 9% of 2-AG hydrolysis, respectively. ABHD6, encoded by the ABHD6 gene, is membrane bound with its active site facing the cytosol, meaning it regulates the intracellular concentration of 2-AG. ABHD12 is encoded by the ABHD12 gene. It’s also membrane bound, but its active site is extracellular, meaning it regulates the immediate extracellular concentration of 2-AG, which can activate CB1 and CB2 receptors, located on the external cell surface as well.^{6, 7.}

The Monoacylglycerol Pathway in the Endocannabinoid System

Given the roles of the endocannabinoid system in regulating appetite, pain, inflammation, and even tumor growth, scientists began developing ways to increase local endocannabinoid concentrations. But now, there is intensified focus on the potential of inhibiting the enzymes that degrade the endocannabinoids instead, such as MAGL for 2-AG and FAAH for anandamide.^{8, 9, 10.}

When too much 2-AG is present in the brain, genetic expression of MAGL is raised in a matter of milliseconds to compensate. Once the level of 2-AG is back under physiological conditions, MAGL levels begin to recede as well. In this manner, the delicate balance of active 2-AG is maintained. If 2-AG levels drop too low, then MAGL levels will decrease accordingly, until the appropriate amount of 2-AG is restored.

This is important because researchers discovered that 2-AG specifically is responsible for the primary role of the endocannabinoid system in two brain processes: Depolarization-induced Suppression of Inhibition (DSI) and Depolarization-induced Suppression of Excitation (DSE). In fact, ABHD12 is the MAGL version that is most vital in controlling the concentration of 2-AG in and around neurons that participate in depolarization-induced changes in synaptic plasticity, such as DSI and DSE.

DSI – which reduces inhibitory signaling – and DSE – which reduces excitatory signaling – are a neuron’s way of controlling its own inputs based on its present input levels. Imagine you’re watching TV, and a commercial comes on that’s significantly louder than the regular program. You’d probably turn the volume down a little bit until the commercial was over. This reduces the intensity of the auditory input your brain is receiving because that input was too intense. Then, when the commercial is over, you’ll turn the volume back up.

1) Too much volume → 2) Volume decreased → 3) Too little volume → 4) Volume increased back to original level

This automatic feedback loop is how our brain stores and retrieves memories. DSI, which suppresses inhibition, occurs when a neuron wants to increase the intensity of its current inputs, forming a stronger synapse and encoding a memory. Likewise, DSE, which suppresses excitation, occurs when a neuron wants to reduce an input because it’s unimportant or should be forgotten.
In both cases, the endocannabinoid 2-AG is released from a target neuron in a reverse “retrograde” direction, where it binds to CB1 receptors located on the neuron that’s sending the inhibitory or excitatory input signals. Activation of CB1 receptors prevents a cell from firing an action potential, so the input neurons stop sending their signals, and balance is restored.^11.
If MAGL levels are too high or too low, then this intricate process can be thrown out of whack. In fact, it’s postulated that the formation of plaque in Alzheimer’s disease and a lack of anchoring proteins in some forms of autism cause their respective neurological deficits because they simultaneously prevent adequate DSI and DSE from taking place.

References:

1. AMA Blankman JL, Simon GM, Cravatt BF. A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol. Chem Biol. 2007;14(12):1347-56.
2. Savinainen JR, Saario SM, Laitinen JT. The serine hydrolases MAGL, ABHD6 and ABHD12 as guardians of 2-arachidonoylglycerol signalling through cannabinoid receptors. Acta Physiol (Oxf). 2012;204(2):267-76.
3. Marrs WR, Blankman JL, Horne EA, et al. The serine hydrolase ABHD6 controls the accumulation and efficacy of 2-AG at cannabinoid receptors. Nat Neurosci. 2010;13(8):951-7.
4. Masanobu Kano, Takako Ohno-Shosaku, Yuki Hashimotodani, Motokazu Uchigashima, Masahiko Watanabe. Endocannabinoid-Mediated Control of Synaptic Transmission 
5. Gulyas, AI, Cravatt, BF, Bracey, MH, Dinh, TP, Piomelli, D., Boscia, F., & Freund, TF. (2004). Segregation of two endocannabinoid-hydrolyzing enzymes into pre- and postsynaptic compartments in the rat hippocampus, cerebellum and amygdala. European Journal of Neuroscience, 20(2), 441-458. http://dx.doi.org/10.1111/j.1460-9568.2004.03428.x
6. Long JZ, Li W, Booker L, et al. Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects. Nat Chem Biol. 2008;5(1):37-44.
7. Dinh TP, Carpenter D, Leslie FM, et al. Brain monoglyceride lipase participating in endocannabinoid inactivation. Proc Natl Acad Sci U S A. 2002;99(16):10819-24.
8. Lau BK, Drew GM, Mitchell VA, Vaughan CW. Endocannabinoid modulation by FAAH and monoacylglycerol lipase within the analgesic circuitry of the periaqueductal grey. Br J Pharmacol. 2014;171(23):5225-36.
9. Burston JJ, Mapp PI, Sarmad S, et al. Robust anti-nociceptive effects of monoacylglycerol lipase inhibition in a model of osteoarthritis pain. Br J Pharmacol. 2016;173(21):3134-3144.
10. Crowe MS, Leishman E, Banks ML, et al. Combined inhibition of monoacylglycerol lipase and cyclooxygenases synergistically reduces neuropathic pain in mice. Br J Pharmacol. 2015;172(7):1700-12.
11. Makara, Judit K, et. al. Selective inhibition of 2-AG hydrolysis enhances endocannabinoid signaling in hippocampus. Nature Neuroscience. https://doi.org/10.1038/nn1521; 10.1038/nn1521