The serine hydrolase ABHD6 controls the accumulation and efficacy of 2-AG at cannabinoid receptors.
The serine hydrolase ABHD6 controls the accumulation and efficacy of 2-AG at cannabinoid receptors.
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DOI：
10.1038/nn.2601
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发表时间：
2010-08
影响因子：
25
通讯作者：
Stella, Nephi
中科院分区：
文献类型：
--
作者：
Marrs, William R.;Blankman, Jacqueline L.;Horne, Eric A.;Thomazeau, Aurore;Lin, Yi Hsing;Coy, Jonathan;Bodor, Agnes L.;Muccioli, Giulio G.;Hu, Sherry Shu-Jung;Woodruff, Grace;Fung, Susan;Lafourcade, Mathieu;Alexander, Jessica P.;Long, Jonathan Z.;Li, Weiwei;Xu, Cong;Moeller, Thomas;Mackie, Ken;Manzoni, Olivier J.;Cravatt, Benjamin F.;Stella, Nephi
内源性大麻素2-花生四烯酸甘油（2-AG）通过激活神经元上的CB 1大麻素受体和小胶质细胞上的CB 2大麻素受体来调节神经传递和神经炎症。水解2-AG的酶，如单酰基甘油脂肪酶，调节2-AG在大麻素受体上的积累和功效。我们发现，最近描述的丝氨酸水解酶α-β-水解酶结构域6（ABHD 6）也控制大麻素受体2-AG的积累和功效。在来自BV-2小胶质细胞系的细胞中，ABHD 6敲低减少了2-AG的水解，并增加了2-AG刺激CB 2介导的细胞迁移的功效。ABHD 6在原代培养的神经元中表达，其抑制导致2-AG的活性依赖性积累。在成年小鼠皮层，ABHD 6位于突触后，其选择性抑制允许诱导CB 1依赖的长期抑郁症，否则阈下刺激。我们的研究结果表明，ABHD 6是2-AG信号传导的限速步骤，因此是内源性大麻素信号传导系统的真正成员。
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 α-β-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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