title: Inhibition of diacylglycerol kinases as a physiological way to promote diacylglycerol signaling.
abstract: Diacylglycerol is a key regulator of cell physiology, controlling the membrane recruitment and activation of signaling molecules. Accordingly, diacylglycerol generation and metabolism are strictly controlled, allowing for localized regulation of its concentration. While the increased production of diacylglycerol upon receptor triggering is well recognized, the modulation of diacylglycerol metabolism by diacylglycerol kinases (DGKs) is less characterized. Some agonists induce DGK activation and recruitment to the plasma membrane, promoting diacylglycerol metabolism to phosphatidic acid. Conversely, several reports indicate that signaling pathways that selectively inhibits DGK isoforms can enhance cellular diacylglycerol levels and signal transduction. For example, the impairment of DGKθ activity by RhoA binding to the catalytic domain represents a conserved mechanism controlling diacylglycerol signaling from Caenorhabditis elegans motoneurons to mammalian hepatocytes. Similarly, DGKα activity is inhibited in lymphocytes by TCR signaling, thus contributing to a rise in diacylglycerol concentration for downstream signaling. Finally, DGKμ activity is inhibited by ischemia-reperfusion-generated reactive oxygen species in airway endothelial cells, promoting diacylglycerol-mediated ion channel opening and edema. In those systems, DGKs provide a gatekeeper function by blunting diacylglycerol levels or possibly establishing permissive domains for diacylglycerol signaling. In this review, I discuss the possible general relevance of DGK inhibition to enhanced diacylglycerol signaling.
authors.affiliation: University "A. Avogadro" del Piemonte Orientale, Department of Translational Medicine, via Solaroli 17, 28100 Novara, Italy. Electronic address: gianluca.baldanzi@med.unipmn.it.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Baldanzi
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology; D019852:Diacylglycerol Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004075:Diglycerides / Q000494:pharmacology*; D006801:Humans; D017382:Reactive Oxygen Species / Q000494:pharmacology; D015398:Signal Transduction
chemical_list: C011439:1,2-diacylglycerol; D004075:Diglycerides; D017382:Reactive Oxygen Species; D019852:Diacylglycerol Kinase