Depolarization-induced rapid generation of 2-arachidonoylglycerol, an endogenous cannabinoid receptor ligand, in rat brain synaptosomes
Depolarization-induced rapid generation of 2-arachidonoylglycerol, an endogenous cannabinoid receptor ligand, in rat brain synaptosomes
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DOI：
10.1093/jb/mvm070
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发表时间：
2007-05-01
影响因子：
2.7
通讯作者：
Sugiura, Takayuki
中科院分区：
文献类型：
--
作者：
Oka, Saori;Arai, Shunsuke;Sugiura, Takayuki
2-花生四烯酰甘油 (2-AG) 是大麻素受体的内源性配体，具有多种有效的生物活性。在这项研究中，我们首先研究了钾诱导的去极化对大鼠脑突触体中 2-AG 水平的影响。我们发现去极化后突触体中产生了大量的 2-AG。值得注意的是，去极化并不影响单酰甘油的其他分子种类的水平。此外，anandamide 的水平非常低，并且在去极化后没有明显变化。由此看来，去极化诱导的加速生成是2-AG的独特特征。我们获得证据表明磷脂酶 C 参与去极化突触体中 2-AG 的生成：磷脂酶 C 抑制剂 U73122 显着减少去极化诱导的 2-AG 生成，并且去极化后二酰基甘油的水平迅速升高。去极化时突触体释放大量 2-AG。有趣的是，用 SR141716A（一种 CB1 受体拮抗剂）处理突触体，增加了去极化突触体中谷氨酸的释放。这些结果强烈表明，大麻素受体的内源配体，即 2-AG，是通过去极化时磷脂代谢增加而产生的，通过作用于 CB1 受体，在减少突触末端谷氨酸释放方面发挥着重要作用。
2-Arachidonoylglycerol (2-AG) is an endogenous ligand for the cannabinoid receptors with a variety of potent biological activities. In this study, we first examined the effects of potassium-induced depolarization on the level of 2-AG in rat brain synaptosomes. We found that a significant amount of 2-AG was generated in the synaptosomes following depolarization. Notably, depolarization did not affect the levels of other molecular species of monoacylglycerols. Furthermore, the level of anandamide was very low and did not change markedly following depolarization. It thus appeared that the depolarization-induced accelerated generation is a unique feature of 2-AG. We obtained evidence that phospholipase C is involved in the generation of 2-AG in depolarized synaptosomes: U73122, a phospholipase C inhibitor, markedly reduced the depolarization-induced generation of 2-AG, and the level of diacylglycerol was rapidly elevated following depolarization. A significant amount of 2-AG was released from synaptosomes upon depolarization. Interestingly, treatment of the synaptosomes with SR141716A, a CB1 receptor antagonist, augmented the release of glutamate from depolarized synaptosomes. These results strongly suggest that the endogenous ligand for the cannabinoid receptors, i.e. 2-AG, generated through increased phospholipid metabolism upon depolarization, plays an important role in attenuating glutamate release from the synaptic terminals by acting on the CB1 receptor.