The Serine Hydrolase ABHD6 Controls the Accumulation and Efficacy of 2-AG at Cannabinoid Receptors

Overview

Journal Nat Neurosci

Date 2010 Jul 27

PMID 20657592

Citations 223

Authors

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 Moller

Ken Mackie

Olivier J Manzoni

Benjamin F Cravatt

Nephi Stella

Affiliations

Soon will be listed here.

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.

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