ABHD6: Its Place in Endocannabinoid Signaling and Beyond

Abstract

The endocannabinoid (eCB) signaling system modulates neurotransmission and inflammation, among other physiological functions. Its newest member, α/β-hydrolase domain-containing 6 (ABHD6), has emerged as a promising therapeutic target to treat several devastating diseases, including epilepsy. Here, we review the molecular mechanisms that mediate and control eCB signaling and, within it, the specific role of ABHD6. We also discuss how ABHD6 controls the abundance of additional lipids and the trafficking of ionotropic receptors to plasma membranes. We finish with several unexplored questions regarding this novel enzyme. Our current understanding of the molecular mechanism and biological function of ABHD6 provides a strong foundation for the development of small-molecule therapeutics to treat devastating diseases.

Keywords: ABHD6; endocannabinoids; enzyme; epilepsy; neuroinflammation; neurons.

Figure 1,. Key Figure. Molecular components involved in the regulation of 2-AG signaling by neurons.

Stimulation of excitatory neurons releases glutamate (blue spheres), activating metabotropic glutamate receptors 1/5 (mGluR_1/5) on the postsynaptic neuron, which couple to G proteins (orange sphere), activate phospholipase C (PLC) and lead to the production of diacylglycerol (DAG) from phosphoinositol bisphosphate (PIP₂). DAG is cleaved by DAG lipase (DGL), which produces 2-AG that acts as 1) paracrine agonist at CB₁ receptors (CB₁R) expressed by excitatory terminals, 2) paracrine agonist at CB₁R expressed by inhibitory terminals that release GABA (red spheres) to activate GABA_A receptors on the post-synaptic neurons and 3) autocrine positive allosteric modulator of GABA_A receptors on the post-synaptic neurons. Excess 2-AG is hydrolyzed to arachidonic acid (AA) and glycerol (not shown) by monoacylglycerol lipase (MGL) in presynaptic neurons or by ABHD6 in postsynaptic neurons. ABHD6 interacts with α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and controls their trafficking to the membrane of post-synaptic compartments.

Figure 2.. ABHD6 activity and inhibition.

The lipid substrate (e.g. 2-AG) is hydrolyzed by ABHD6 (purple shape) containing a catalytic triad made by amino acids S148, D278 and H306 and leads to the release of arachidonic acid (AA) and glycerol. Fatty-acid based inhibitors (e.g. UCM710) compete with the lipid substrate whereas irreversible carbamates inhibitors (KT-182) and reversible inhibitors (MJN193) interact with catalytic triad.

Figure 3.. Multifunctional activity of ABHD6.

A. Rise in intracellular calcium concentration activates diacylglycerol lipase (DGL) that cleaves diacylglycerol (DAG) into 2-AG. ABHD6 hydrolyzes 2-AG into arachidonic acid (AA) and glycerol (not shown). Thus, ABHD6 controls the activity-dependent 2-AG accumulation and eventual activation of cannabinoid receptors CB₁R and CB₂R and GABA_A receptors. B. ABHD6 controls the hydrolysis of monoacylglycerols (MAG) into fatty acids (FA). MAG accumulation might module the activity of unknown receptors targets and/or modify lipid membrane composition. C. ABHD6 acts as a chaperone to traffic AMPA receptors to the plasma membrane.