Chemical Proteomics Maps Brain Region Specific Activity of Endocannabinoid Hydrolases.
ACS Chem. Biol.. 2017-02-13; 12(3): 852-861
DOI: 10.1021/acschembio.6b01052
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1. ACS Chem Biol. 2017 Mar 17;12(3):852-861. doi: 10.1021/acschembio.6b01052. Epub
2017 Feb 13.
Chemical Proteomics Maps Brain Region Specific Activity of Endocannabinoid
Hydrolases.
Baggelaar MP(1), van Esbroeck AC(1), van Rooden EJ(1), Florea BI(2), Overkleeft
HS(2), Marsicano G(3), Chaouloff F(3), van der Stelt M(1).
Author information:
(1)Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden
University , Leiden, The Netherlands.
(2)Department of Bio-organic Synthesis, Leiden Institute of Chemistry, Leiden
University , Leiden, The Netherlands.
(3)Plateforme de Chimie Analytique, NeuroCentre INSERM U862 , Bordeaux, France.
The biosynthetic and catabolic enzymes of the endocannabinoids tightly regulate
endocannabinoid-mediated activation of the cannabinoid CB1 receptor. Monitoring
the activities of these endocannabinoid hydrolases in different brain regions is,
therefore, key to gaining insight into spatiotemporal control of CB1
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 CB1 receptor was studied. No difference in the
enzymatic activity was found in the cerebellum, striatum, frontal cortex, and
hippocampus of CB1 receptor knockout animals compared to wild type mice. Our
results are in line with previous reports and indicate that the CB1 receptor
exerts no regulatory control over the basal production and degradation of
endocannabinoids and that genetic deletion of the CB1 receptor does not induce
compensatory mechanisms in endocannabinoid hydrolase activity.
DOI: 10.1021/acschembio.6b01052
PMID: 28106377 [Indexed for MEDLINE]