In addition to furthering our understanding of the propertie

In addition to furthering our understanding of the properties of diacylglycerol kinases, there may be relevance of these findings to the role of endocannabinoids in neuronal function. 2-AG is an endocannabinoid that can arise from the DAG lipase catalyzed cleavage of SAG, the preferred substrate of DGKε. Another route of metabolism of SAG is by DGKε-catalyzed phosphorylation to generate SAPA. In DGKε knockout mice, the conversion of this particular species of diacylglycerol to phosphatidic BRD 7552 australia is reduced [17]. Consequently, an alternative path for the SAG metabolism would be its conversion to the endocannabinoid, 2-AG by the DAG lipase. Based on our findings on the inhibitory property of 2-AG on DGKε, there could be a weak feed-forward effect of 2-AG on its own formation as a result of its inhibition of DGKε. 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 acid (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].