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

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 Möller; Ken MacKie; Olivier J. Manzoni; Benjamin F. Cravatt; Nephi Stella

doi:10.1038/nn.2601

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

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 Möller, Ken MacKie, Olivier J. Manzoni, Benjamin F. CravattNephi Stella

Department of Psychology

Research output: Contribution to journal › Article › peer-review

380 Citations (Scopus)

Abstract

The endocannabinoid 2-arachidonoylglycerol (2-AG) regulates neurotransmission and neuroinflammation by activating CB 1 cannabinoid receptors on neurons and CB 2 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 Î ±-Î 2-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 CB 2-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 CB 1-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.

Original language	English
Pages (from-to)	951-957
Number of pages	7
Journal	Nature Neuroscience
Volume	13
Issue number	8
DOIs	https://doi.org/10.1038/nn.2601
Publication status	Published - 2010 Aug

All Science Journal Classification (ASJC) codes

General Neuroscience

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10.1038/nn.2601

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Marrs, W. R., Blankman, J. L., Horne, E. A., Thomazeau, A., Lin, Y. H., Coy, J., Bodor, A. L., Muccioli, G. G., Hu, S. S. J., Woodruff, G., Fung, S., Lafourcade, M., Alexander, J. P., Long, J. Z., Li, W., Xu, C., Möller, T., MacKie, K., Manzoni, O. J., ... Stella, N. (2010). The serine hydrolase ABHD6 controls the accumulation and efficacy of 2-AG at cannabinoid receptors. Nature Neuroscience, 13(8), 951-957. https://doi.org/10.1038/nn.2601

@article{a40776682e9e48648646d6ecd01e46ae,

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 CB 1 cannabinoid receptors on neurons and CB 2 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 {\^I} ±-{\^I} 2-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 CB 2-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 CB 1-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.",

author = "Marrs, {William R.} and Blankman, {Jacqueline L.} and Horne, {Eric A.} and Aurore Thomazeau and Lin, {Yi Hsing} and Jonathan Coy and Bodor, {Agnes L.} and Muccioli, {Giulio G.} and Hu, {Sherry Shu Jung} and Grace Woodruff and Susan Fung and Mathieu Lafourcade and Alexander, {Jessica P.} and Long, {Jonathan Z.} and Weiwei Li and Cong Xu and Thomas M{\"o}ller and Ken MacKie and Manzoni, {Olivier J.} and Cravatt, {Benjamin F.} and Nephi Stella",

note = "Funding Information: This work was supported by grants from the National Institute on Drug Abuse (DA14486 and DA26430 to N.S., DA017259, DA009789 and DA025285 to B.F.C. and DA026161 to J.L.B.) and from the National Institute of General Medical Sciences (PHS NRSA 2T32 GM007270 to W.R.M.).",

year = "2010",

month = aug,

doi = "10.1038/nn.2601",

language = "English",

volume = "13",

pages = "951--957",

journal = "Nature Neuroscience",

issn = "1097-6256",

publisher = "Nature Publishing Group",

number = "8",

}

Marrs, WR, Blankman, JL, Horne, EA, Thomazeau, A, Lin, YH, Coy, J, Bodor, AL, Muccioli, GG, Hu, SSJ, Woodruff, G, Fung, S, Lafourcade, M, Alexander, JP, Long, JZ, Li, W, Xu, C, Möller, T, MacKie, K, Manzoni, OJ, Cravatt, BF & Stella, N 2010, 'The serine hydrolase ABHD6 controls the accumulation and efficacy of 2-AG at cannabinoid receptors', Nature Neuroscience, vol. 13, no. 8, pp. 951-957. https://doi.org/10.1038/nn.2601

TY - JOUR

T1 - The serine hydrolase ABHD6 controls the accumulation and efficacy of 2-AG at cannabinoid receptors

AU - Marrs, William R.

AU - Blankman, Jacqueline L.

AU - Horne, Eric A.

AU - Thomazeau, Aurore

AU - Lin, Yi Hsing

AU - Coy, Jonathan

AU - Bodor, Agnes L.

AU - Muccioli, Giulio G.

AU - Hu, Sherry Shu Jung

AU - Woodruff, Grace

AU - Fung, Susan

AU - Lafourcade, Mathieu

AU - Alexander, Jessica P.

AU - Long, Jonathan Z.

AU - Li, Weiwei

AU - Xu, Cong

AU - Möller, Thomas

AU - MacKie, Ken

AU - Manzoni, Olivier J.

AU - Cravatt, Benjamin F.

AU - Stella, Nephi

N1 - Funding Information: This work was supported by grants from the National Institute on Drug Abuse (DA14486 and DA26430 to N.S., DA017259, DA009789 and DA025285 to B.F.C. and DA026161 to J.L.B.) and from the National Institute of General Medical Sciences (PHS NRSA 2T32 GM007270 to W.R.M.).

PY - 2010/8

Y1 - 2010/8

N2 - The endocannabinoid 2-arachidonoylglycerol (2-AG) regulates neurotransmission and neuroinflammation by activating CB 1 cannabinoid receptors on neurons and CB 2 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 Î ±-Î 2-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 CB 2-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 CB 1-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.

AB - The endocannabinoid 2-arachidonoylglycerol (2-AG) regulates neurotransmission and neuroinflammation by activating CB 1 cannabinoid receptors on neurons and CB 2 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 Î ±-Î 2-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 CB 2-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 CB 1-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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JO - Nature Neuroscience

JF - Nature Neuroscience

IS - 8

ER -

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

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