1. Nat Neurosci. 2010 Aug;13(8):951-7. Epub 2010 Jul 25.

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

Marrs WR, Blankman JL, Horne EA, Thomazeau A, Lin YH, Coy J, Bodor AL, Muccioli
GG, Hu SS, Woodruff G, Fung S, Lafourcade M, Alexander JP, Long JZ, Li W, Xu C,
Möller T, Mackie K, Manzoni OJ, Cravatt BF, Stella N.

Neurobiology and Behavior Graduate Program, University of Washington, Seattle,
Washington, USA.

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
alpha-beta-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.


PMCID: PMC2970523 [Available on 2011/2/1]
PMID: 20657592 [PubMed - indexed for MEDLINE]