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Nat Neurosci. 2010 Aug;13(8):951-7. doi: 10.1038/nn.2601. Epub 2010 Jul 25.

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

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1
Neurobiology and Behavior Graduate Program, University of Washington, Seattle, Washington, USA.

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 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.

PMID:
20657592
PMCID:
PMC2970523
DOI:
10.1038/nn.2601
[Indexed for MEDLINE]
Free PMC Article

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