Monoacylglycerol Lipase Activity Is a Critical Modulator of the Tone and Integrity of the Endocannabinoid System
Monoacylglycerol Lipase Activity Is a Critical Modulator of the Tone and Integrity of the Endocannabinoid System
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DOI：
10.1124/mol.110.068304
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发表时间：
2010-12-01
影响因子：
3.6
通讯作者：
Samad, Tarek A.
中科院分区：
文献类型：
--
作者：
Chanda, Pranab K.;Gao, Ying;Samad, Tarek A.
内源性大麻素是作为大麻素受体CB 1和CB 2的天然配体的脂质分子。它们调节一系列不同的生理过程，如疼痛、认知、食欲和情绪状态，其水平和功能受到酶的生物合成和降解的严格调节。2-花生四烯酰甘油（2-AG）是大脑中含量最丰富的内源性大麻素，据信主要由丝氨酸水解酶单酰基甘油脂肪酶（MAGL）水解。尽管2-AG在体外结合并激活大麻素受体，但当在体内施用时，由于其快速的catenorization，其仅诱导短暂的大麻模拟效应。在这里，我们使用小鼠模型与靶向破坏的MAGL基因，MAGL是2-AG水解在体内的主要调节剂。缺乏MAGL的小鼠在神经系统中表现出显著降低的2-AG水解酶活性和高度升高的2-AG水平。MAGL活性的缺乏和随后2-AG水平的长期升高导致脑CB 1受体的脱敏，CB 1激动剂的大麻拟似作用显著降低。同样与CB 1脱敏一致的是，MAGL缺陷小鼠在神经性和炎性疼痛敏感性方面没有显示出改变。这些发现提供了第一个体内遗传证据，即MAGL是2-AG水平和信号传导的主要调节剂，并揭示了2-AG在调节CB 1受体敏化和内源性大麻素张力中的关键作用。
Endocannabinoids are lipid molecules that serve as natural ligands for the cannabinoid receptors CB1 and CB2. They modulate a diverse set of physiological processes such as pain, cognition, appetite, and emotional states, and their levels and functions are tightly regulated by enzymatic biosynthesis and degradation. 2-Arachidonoylglycerol (2-AG) is the most abundant endocannabinoid in the brain and is believed to be hydrolyzed primarily by the serine hydrolase monoacylglycerol lipase (MAGL). Although 2-AG binds and activates cannabinoid receptors in vitro, when administered in vivo, it induces only transient cannabimimetic effects as a result of its rapid catabolism. Here we show using a mouse model with a targeted disruption of the MAGL gene that MAGL is the major modulator of 2-AG hydrolysis in vivo. Mice lacking MAGL exhibit dramatically reduced 2-AG hydrolase activity and highly elevated 2-AG levels in the nervous system. A lack of MAGL activity and subsequent long-term elevation of 2-AG levels lead to desensitization of brain CB1 receptors with a significant reduction of cannabimimetic effects of CB1 agonists. Also consistent with CB1 desensitization, MAGL-deficient mice do not show alterations in neuropathic and inflammatory pain sensitivity. These findings provide the first genetic in vivo evidence that MAGL is the major regulator of 2-AG levels and signaling and reveal a pivotal role for 2-AG in modulating CB1 receptor sensitization and endocannabinoid tone.