The serine hydrolase ABHD6 controls the accumulation and efficacy of 2-AG at cannabinoid receptors.
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.
Marrs
William R
WR
Neurobiology and Behavior Graduate Program, University of Washington, Seattle, Washington, USA.
Blankman
Jacqueline L
JL
Horne
Eric A
EA
Thomazeau
Aurore
A
Lin
Yi Hsing
YH
Coy
Jonathan
J
Bodor
Agnes L
AL
Muccioli
Giulio G
GG
Hu
Sherry Shu-Jung
SS
Woodruff
Grace
G
Fung
Susan
S
Lafourcade
Mathieu
M
Alexander
Jessica P
JP
Long
Jonathan Z
JZ
Li
Weiwei
W
Xu
Cong
C
Möller
Thomas
T
Mackie
Ken
K
Manzoni
Olivier J
OJ
Cravatt
Benjamin F
BF
Stella
Nephi
N
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
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