The serine hydrolase ABHD6 controls the accumulation and efficacy of 2-AG at cannabinoid receptors

William R. Marrs, Jacqueline L. Blankman, Eric A. Horne, Aurore Thomazeau, Yi Hsing Lin, Jonathan Coy, Agnes L. Bodor, Giulio G. Muccioli, Sherry Shu Jung Hu, Grace Woodruff, Susan Fung, Mathieu Lafourcade, Jessica P. Alexander, Jonathan Z. Long, Weiwei Li, Cong Xu, Thomas Möller, Ken MacKie, Olivier J. Manzoni, Benjamin F. CravattNephi Stella

Research output: Contribution to journalArticlepeer-review

290 Citations (Scopus)

Abstract

The endocannabinoid 2-arachidonoylglycerol (2-AG) regulates neurotransmission and neuroinflammation by activating CB 1 cannabinoid receptors on neurons and CB 2 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 Î ±-Î 2-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 CB 2-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 CB 1-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.

Original languageEnglish
Pages (from-to)951-957
Number of pages7
JournalNature Neuroscience
Volume13
Issue number8
DOIs
Publication statusPublished - 2010 Aug

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

Fingerprint Dive into the research topics of 'The serine hydrolase ABHD6 controls the accumulation and efficacy of 2-AG at cannabinoid receptors'. Together they form a unique fingerprint.

Cite this