Diacylglycerol (DAG) Signaling Role in Synaptic Plasticity

Introduction of DAG

Diacylglycerol (DAG) is made up of a glycerol backbone esterified with two fatty acids, giving rise to the formation of three stereochemical isoforms namely sn-1,2-DAG, sn1,3-DAG, and sn-2,3-DAG. Among the three isomers, 1,3-DAG is thermodynamically more stable as compared to 1,2-(2,3-)-DAG due to the steric hindrance effect. Hence, it is common to end up with an equilibrium mixture of 30-40% 1,2-(2,3-) DAG and 60-70% 1,3-DAG. sn-1,2-Diacylglycerol is the most studied diradylglycerol in mammalian cells. The lipid plays a key role in lipid biosynthesis, in particular of phospholipids and triglycerides, but its individual significance is a consequence of its identification as the physiological activator of protein kinase C (PKC). There are three diradylglycerols in mammalian cells, alkyl, acyl-glycerol, alkenyl, acyl-glycerol, and DAG.

Fig.1 Metabolic pathway of DAG digestion. (Lee, 2020)

Introduction of Synaptic Plasticity

This plasticity determines the ability to alter responsiveness under the influence of successive stimuli, either directly or in association with other factors. Plasticity is the fundamental and most specific functional characteristic of nerve cells, switching on diverse changes in the functioning of neurons. The plastic alterations result in prolonged cellular and synaptic function modifications, which allow us to explain simple modifications of behavioral reactions. The plasticity of the neuron can manifest in the form of a temporary alteration in its responsiveness, either depression or an enhancement. These forms of plasticity, in turn, can be classified into synaptic forms presupposing previous synaptic activation and nonsynaptic forms, which occur when plasticity arises after direct (chemical or electrical) stimulation of the neuron.

DAG Signaling Role in Synaptic Plasticity

It has been long recognized that lipids play important roles in a number of physiological functions. The discovery of the phosphatidylinositol (PtdIns) cycle in neurons accelerated research on the role of lipids in neurobiology. The canonical view of the PtdIns cycle involves the stimulated hydrolysis of phosphatidylinositol-(4,5) bisphosphate PtdIns(4,5)P2 which leads to the generation of inositol (1,4,5) trisphosphate (IP3) and DAG. This system, along with an influx of extracellular calcium provides a mechanism for stimulated increases in calcium and DAG during neuronal stimulation. The DAG generated in this cycle is converted to phosphatidic acid (PtdOH) which is subsequently used for the re-synthesis of PtdIns. Enzymes capable of coordinately regulating the levels of these two lipids are the diacylglycerol kinases (DGKs). These enzymes are organized into five classes or Types based upon similarities in their primary sequence. All DGKs catalyze the transfer of the γ-phosphate of ATP to the hydroxyl group of DAG thereby generating PtdOH while reducing DAG. The notion that these enzymes play important neuronal roles is supported by the observations that eight of the 10 mammalian DGK isozymes are readily detected in the mammalian central nervous system (CNS).

Fig.2 Possible distinct functions of DGK isoforms, and their general role as a coordinator of synaptic plasticity. (Lee, 2016)

Table 1. Involvement of DGK isoforms in several forms of synaptic plasticity.

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Reference

1. Lee, D., et al. Diacylglycerol Kinases in the Coordination of Synaptic Plasticity. Front Cell Dev Biol. 2016, 4: 92.