학술논문
The serine hydrolase ABHD6 controls the accumulation and efficacy of 2-AG at cannabinoid receptors.
Document Type
Article
Author
Marrs, William R.; Blankman, Jacqueline L.; Horne, Eric A.; Thomazeau, Aurore; Yi Hsing Lin; Coy, Jonathan; Bodor, Agnes L.; Muccioli, Giulio G.; Sherry Shu-Jung Hu; Woodruff, Grace; Susan Fung; Lafourcade, Mathieu; Alexander, Jessica P; Long, Jonathan Z; Weiwei Li; Cong Xu; Möller, Thomas; Mackie, Ken; Manzoni, Olivier J.; Cravatt, Benjamin F.
Source
Subject
*NEURAL transmission
*HYDROLASES
*MICROGLIA
*NEURONS
*MENTAL depression
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Language
ISSN
1097-6256
Abstract
The endocannabinoid 2-arachidonoylglycerol (2-AG) regulates neurotransmission and neuroinflammation by activating CB1 cannabinoid receptors on neurons and CB2 cannabinoid receptors on microglia. Enzymes that hydrolyze 2-AG, such as monoacylglycerol lipase, regulate the accumulation and efficacy of 2-AG at cannabinoid receptors. We found that the recently described serine hydrolase α-β-hydrolase domain 6 (ABHD6) also controls the accumulation and efficacy of 2-AG at cannabinoid receptors. In cells from the BV-2 microglia cell line, ABHD6 knockdown reduced hydrolysis of 2-AG and increased the efficacy with which 2-AG can stimulate CB2-mediated cell migration. ABHD6 was expressed by neurons in primary culture and its inhibition led to activity-dependent accumulation of 2-AG. In adult mouse cortex, ABHD6 was located postsynaptically and its selective inhibition allowed the induction of CB1-dependent long-term depression by otherwise subthreshold stimulation. Our results indicate that ABHD6 is a rate-limiting step of 2-AG signaling and is therefore a bona fide member of the endocannabinoid signaling system. [ABSTRACT FROM AUTHOR]