期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 113, 期 1, 页码 26-33出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1522364112
关键词
endocannabinoid; lipase; inhibitor; nervous system
资金
- National Institutes of Health [DA033760, GM109315, DA035217, MH101146]
- Chinese Scholarship Council
- Dutch Research Council-Chemical Sciences ECHO grant
- ECHO-STIP Grant
Diacylglycerol lipases (DAGL alpha and DAGL beta) 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 DAGL alpha 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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