Open AccessChemical Proteomics Maps Brain Region Specific Activity of Endocannabinoid Hydrolases
Author(s) -
Marc P. Baggelaar,
Annelot C. M. van Esbroeck,
Eva J. van Rooden,
Bogdan I. Florea,
Herman S. Overkleeft,
Giovanni Marsicano,
Francis Chaouloff,
Mario van der Stelt
Publication year - 2017
Publication title -
acs chemical biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.899
H-Index - 111
eISSN - 1554-8937
pISSN - 1554-8929
DOI - 10.1021/acschembio.6b01052
Subject(s) - monoacylglycerol lipase , endocannabinoid system , cannabinoid receptor , diacylglycerol lipase , cannabinoid , serine hydrolase , fatty acid amide hydrolase , depolarization induced suppression of inhibition , hippocampus , biology , biochemistry , chemistry , receptor , neuroscience , serine , enzyme , agonist
The biosynthetic and catabolic enzymes of the endocannabinoids tightly regulate endocannabinoid-mediated activation of the cannabinoid CB 1 receptor. Monitoring the activities of these endocannabinoid hydrolases in different brain regions is, therefore, key to gaining insight into spatiotemporal control of CB 1 receptor-mediated physiology. We have employed a comparative chemical proteomics approach to quantitatively map the activity profile of endocannabinoid hydrolases in various mouse brain regions at the same time. To this end, we used two different activity-based probes: fluorophosphonate-biotin (FP-biotin), which quantifies FAAH, ABHD6, and MAG-lipase activity, and MB108, which detects DAGL-α, ABHD4, ABHD6, and ABHD12. In total, 32 serine hydrolases were evaluated in the frontal cortex, hippocampus, striatum, and cerebellum. Comparison of endocannabinoid hydrolase activity in the four brain regions revealed that FAAH activity was highest in the hippocampus, and MAGL activity was most pronounced in the frontal cortex, whereas DAGL-α was most active in the cerebellum. Comparison of the activity profiles with a global proteomics data set revealed pronounced differences. This could indicate that post-translational modification of the endocannabinoid hydrolases is important to regulate their activity. Next, the effect of genetic deletion of the CB 1 receptor was studied. No difference in the enzymatic activity was found in the cerebellum, striatum, frontal cortex, and hippocampus of CB 1 receptor knockout animals compared to wild type mice. Our results are in line with previous reports and indicate that the CB 1 receptor exerts no regulatory control over the basal production and degradation of endocannabinoids and that genetic deletion of the CB 1 receptor does not induce compensatory mechanisms in endocannabinoid hydrolase activity.