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Ogasawara, Daisuke; Deng, Hui; Viader, Andreu; Baggelaar, Marc P.; Breman, Arjen; den Dulk, Hans; van den Nieuwendijk, Adrianus M. C. H.; Soethoudt, Marjolein; van der Wel, Tom; Zhou, Juan; Overkleeft, Herman S.; Sanchez-Alavez, Manuel; Mori, Simone; Nguyen, William; Conti, Bruno; Liu, Xiaojie; Chen, Yao; Liu, Qing-song; Cravatt, Benjamin F.; van der Stelt, Mario
Proceedings of the National Academy of Sciences - PNAS, 01/2016, Letnik: 113, Številka: 1Journal Article
Diacylglycerol lipases (DAGLα and DAGLβ) convert diacylglycerol to the endocannabinoid 2-arachidonoylglycerol. Our understanding of DAGL function has been hindered by a lack of chemical probes that can perturb these enzymes in vivo. Here, we report a set of centrally active DAGL inhibitors and a structurally related control probe and their use, in combination with chemical proteomics and lipidomics, to determine the impact of acute DAGL blockade on brain lipid networks in mice. Within 2 h, DAGL inhibition produced a striking reorganization of bioactive lipids, including elevations in DAGs and reductions in endocannabinoids and eicosanoids. We also found that DAGLα is a short half-life protein, and the inactivation of DAGLs disrupts cannabinoid receptor-dependent synaptic plasticity and impairs neuroinflammatory responses, including lipopolysaccharide-induced anapyrexia. These findings illuminate the highly interconnected and dynamic nature of lipid signaling pathways in the brain and the central role that DAGL enzymes play in regulating this network.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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in: SICRIS
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