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  • This pathway appears to have importance in epilepsy


    This pathway appears to have importance in epilepsy. DGKε(−/−) mice had significantly fewer motor seizure and epileptic events compared with DGKε(+/+) mice [18]. This could be explained by the fact that in the knockout mice a greater fraction of the SAG would be converted to 2-AG. 2-AG itself is known to have anticonvulsive effects through activation of cannabinoid receptors [19]. Pharmacological studies have shown that it is the type 1 cannabinoid receptor that is linked to epileptic events [20]. The natural resistance of certain species to epileptic seizures has been suggested to be a consequence of their high level of expression of type 1 cannabinoid receptors [21]. The formation of 2-AG resulting in the activation of type 1 cannabinoid receptors will be affected by the activity of DGKε that reduces the fraction of SAG converted to 2-AG. The present study describes the relationship between 2-AG and DGKs that could impinge on neuronal function.
    Acknowledgements This work was supported in part by a grant from the Natural Sciences and Engineering Research Council of Canada, grant 9848 (to R.M.E.) and from the National Institutes of Health grants R01-CA95463 (to M.K.T.).
    Introduction Diacylglycerol kinase (DGK) is a lipid-metabolizing enzyme that phosphorylates diacylglycerol (DG) to produce phosphatidic Coumarin (PA). DG and PA act as lipid secondary messengers in a wide variety of biological processes in mammalian cells [[1], [2], [3]]. For example, DG serves to activate several signaling proteins including conventional protein kinase Cs (cPKCs) and novel PKCs (nPKCs) [[4], [5], [6]]. PA also regulates a number of signaling proteins such as phosphatidylinositol (PI)-4-phosphate 5-kinase and mammalian targets of rapamycin (mTOR) [[7], [8], [9]]. Thus, DGK plays an important role in signal transduction by modulating the balance between these signaling lipids [10,11]. To date, ten mammalian DGK isozymes (α, β, γ, δ, η, κ, ε, ζ, ι and θ) have been identified, and these isozymes are subdivided into five groups according to their structural features [10,11]. Type II DGKs consist of the δ, η and κ isoforms [12,13]. Additionally, alternatively spliced forms of DGKδ (δ1 and δ2) [14] and η (η1−η4) [[15], [16], [17]] have been found. Structural characteristics of type II DGKs commonly include the presence of the pleckstrin homology (PH) domain at the N-terminus, four coiled-coil structures and a separated catalytic region [10,12]. DGKδ is abundantly expressed in skeletal muscle [18], which is a major insulin-target organ for glucose disposal [19]. Chibalin et al. have demonstrated that a decrease in DGKδ expression increases the severity of type 2 diabetes [20]. Moreover, acute high glucose exposure increases DGKδ activity in L6 skeletal muscle cells, followed by a reduction of PKCα activity and transactivation of the insulin receptor signal [21]. These studies indicate that DGKδ positively controls glucose uptake in skeletal muscle by attenuating PKC activity. In addition, our recent study showed that DGKδ in high glucose-stimulated C2C12 myoblasts preferentially phosphorylates palmitic acid (16:0)-containing DG species derived from the phosphatidylcholine-specific phospholipase C (PC-PLC) pathway, suggesting that the PC-PLC/DGKδ pathway plays an important role in insulin signaling and glucose uptake [22,23]. DGKδ is a key enzyme in glucose uptake in skeletal muscle, as described above. Interestingly, in C2C12 myotubes, myristic acid (14:0) significantly increases DGKδ levels and glucose uptake in a DGKδ-dependent manner [24,25]. Moreover, our recent study demonstrated that myristic acid increases DGKδ levels in skeletal muscle of Nagoya–Shibata–Yasuda (NSY) mice, which are widely used as a model for type 2 diabetes, and reduced the insulin-responsive blood glucose levels of the mice [26]. These studies indicated that up-regulation of DGKδ is important for the prevention and treatment of type 2 diabetes.