Rapid and profound rewiring of brain lipid signaling networks by acute diacylglycerol lipase inhibition.

Autor:	Ogasawara D; Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037;, Deng H; Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, 2333 CC Leiden, The Netherlands;, Viader A; Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037;, Baggelaar MP; Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, 2333 CC Leiden, The Netherlands;, Breman A; Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, 2333 CC Leiden, The Netherlands;, den Dulk H; Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, 2333 CC Leiden, The Netherlands;, van den Nieuwendijk AM, Soethoudt M; Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, 2333 CC Leiden, The Netherlands;, van der Wel T; Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, 2333 CC Leiden, The Netherlands;, Zhou J; Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, 2333 CC Leiden, The Netherlands;, Overkleeft HS; Department of Bio-organic Synthesis, Leiden Institute of Chemistry, Leiden University, 2333 CC Leiden, The Netherlands;, Sanchez-Alavez M; Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037;, Mori S, Nguyen W; Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037;, Conti B; Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037;, Liu X; Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226., Chen Y; Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226., Liu QS; Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226., Cravatt BF; Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037; cravatt@scripps.edu m.van.der.stelt@chem.leidenuniv.nl., van der Stelt M; Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, 2333 CC Leiden, The Netherlands; cravatt@scripps.edu m.van.der.stelt@chem.leidenuniv.nl.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2016 Jan 05; Vol. 113 (1), pp. 26-33. Date of Electronic Publication: 2015 Dec 14.
DOI:	10.1073/pnas.1522364112
Abstrakt:	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.
Databáze:	MEDLINE
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