title: The serine hydrolase ABHD6 controls the accumulation and efficacy of 2-AG at cannabinoid receptors.
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.
authors.affiliation: Neurobiology and Behavior Graduate Program, University of Washington, Seattle, Washington, USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Marrs
authors.forename: Jacqueline L
authors.initials: JL
authors.lastname: Blankman
authors.forename: Eric A
authors.initials: EA
authors.lastname: Horne
authors.forename: Aurore
authors.initials: A
authors.lastname: Thomazeau
authors.forename: Yi Hsing
authors.initials: YH
authors.lastname: Lin
authors.forename: Jonathan
authors.initials: J
authors.lastname: Coy
authors.forename: Agnes L
authors.initials: AL
authors.lastname: Bodor
authors.forename: Giulio G
authors.initials: GG
authors.lastname: Muccioli
authors.forename: Sherry Shu-Jung
authors.initials: SS
authors.lastname: Hu
authors.forename: Grace
authors.initials: G
authors.lastname: Woodruff
authors.forename: Susan
authors.initials: S
authors.lastname: Fung
authors.forename: Mathieu
authors.initials: M
authors.lastname: Lafourcade
authors.forename: Jessica P
authors.initials: JP
authors.lastname: Alexander
authors.forename: Jonathan Z
authors.initials: JZ
authors.lastname: Long
authors.forename: Weiwei
authors.initials: W
authors.lastname: Li
authors.forename: Cong
authors.initials: C
authors.lastname: Xu
authors.forename: Thomas
authors.initials: T
authors.lastname: Möller
authors.forename: Ken
authors.initials: K
authors.lastname: Mackie
authors.forename: Olivier J
authors.initials: OJ
authors.lastname: Manzoni
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
authors.forename: Nephi
authors.initials: N
authors.lastname: Stella
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D019556:COS Cells; D002460:Cell Line; D002465:Cell Movement; D002522:Chlorocebus aethiops; D063388:Endocannabinoids; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D055785:Gene Knockdown Techniques; D005989:Glycerides / Q000378:metabolism*; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism; D046529:Microscopy, Electron, Transmission; D008994:Monoacylglycerol Lipases / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D018408:Patch-Clamp Techniques; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism*; D043885:Receptor, Cannabinoid, CB2 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection
chemical_list: D001095:Arachidonic Acids; D063388:Endocannabinoids; D005989:Glycerides; D012333:RNA, Messenger; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; C094503:glyceryl 2-arachidonate; C527261:ABHD6 protein, mouse; D008994:Monoacylglycerol Lipases