The diacylglycerol lipases: structure, regulation and roles in and beyond endocannabinoid signalling

Abstract

The diacylglycerol lipases (DAGLs) hydrolyse diacylglycerol to generate 2-arachidonoylglycerol (2-AG), the most abundant ligand for the CB 1 and CB 2 cannabinoid receptors in the body. DAGL-dependent endocannabinoid signalling regulates axonal growth and guidance during development, and is required for the generation and migration of new neurons in the adult brain. At developed synapses, 2-AG released from postsynaptic terminals acts back on presynaptic CB 1 receptors to inhibit the secretion of both excitatory and inhibitory neurotransmitters, with this DAGL-dependent synaptic plasticity operating throughout the nervous system. Importantly, the DAGLs have functions that do not involve cannabinoid receptors. For example, 2-AG is the precursor of arachidonic acid in a pathway that maintains the level of this essential lipid in the brain and other organs. This pathway also drives the cyclooxygenase-dependent generation of inflammatory prostaglandins in the brain, which has recently been implicated in the degeneration of dopaminergic neurons in Parkinson's disease. Remarkably, we still know very little about the mechanisms that regulate DAGL activity-however, key insights can be gleaned by homology modelling against other a/b hydrolases and from a detailed examination of published proteomic studies and other databases. These identify a regulatory loop with a highly conserved signature motif, as well as phosphorylation and palmitoylation as post-translational mechanisms likely to regulate function.

Rapid and profound rewiring of brain lipid signaling networks by acute diacylglycerol lipase inhibition

“…S3). Finally, DH376 and DO34 showed KT172 (1) DO34 (5) DH376 (4) DO53 (8) minimal and negligible binding, respectively, to cannabinoid CB 1 (CB 1 R) and CB 2 (CB 2 R) receptors as measured with radioligand binding assays (IC 50 values > 1 μM) (SI Appendix, Fig. S4).…”

“…Although DAGLα −/− and DAGLβ −/− mice have provided valuable models for investigating the in vivo effects of disrupting endocannabinoid biosynthesis, DAGLα plays an important role in brain development (13) and chronic alterations in endocannabinoid tone can lead to substantial CB 1 R adaptations in the CNS (45,46) and peripheral tissues (47). The endocannabinoid system also crosstalks with several other bioactive lipid pathways (8,48,49). The extent to which this larger lipid network is dynamically regulated in the CNS by acute disruption of endocannabinoid synthesis remains unknown.…”

“…This "on-demand" model for production implicates lipid biosynthetic enzymes as major regulators of chemical signaling in the central nervous system (CNS). In support of this premise, the enzymes that produce several classes of lipid transmitters, including lysophospholipids (6), eicosanoids (7), and endocannabinoids (8,9), are highly expressed in the nervous system and play important roles in brain development, synaptic plasticity, and the modulation of complex behaviors. For example, the diacylglycerol (DAG) lipase enzymes DAGLα and DAGLβ (10) produce the endocannabinoid 2-arachidonoylglycerol (2-AG) (11,12), and the constitutive genetic disruption of DAGLα lowers brain 2-AG and arachidonic acid (AA) content (13,14), resulting in impaired synaptic plasticity (13,14), hypophagia (15), enhanced anxiety and fear responses (16,17), and propensity for spontaneous seizures (15).…”

Diacylglycerol mediates regulation of TASK potassium channels by Gq-coupled receptors

“…5d,f). Overexpression of DAG lipase alpha (DGLa 35 ) also strongly attenuated the receptor-induced accumulation of DAG (Fig. 5b,c).…”

“…DAG is also turned over by DGLs to generate the endocannabinoid 2-AG. Although their signalling function has been considered mostly in terms of production of the signalling lipids 2-AG and AA 35 , a role in regulating TASK channels by curtailing DAG signals should be considered, given that experimental overexpression of DGLa strongly affected DAG transients (Fig. 5).…”