Pharmacological evidence for the involvement of diacylglycerol lipase in depolarization-induced endocanabinoid release
Pharmacological evidence for the involvement of diacylglycerol lipase in depolarization-induced endocanabinoid release
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DOI：
10.1016/j.neuropharm.2007.06.002
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发表时间：
2008-01-01
影响因子：
4.7
通讯作者：
Kano, Masanobu
中科院分区：
文献类型：
--
作者：
Hashimotodani, Yuki;Ohno-Shosaku, Takako;Kano, Masanobu
去极化诱导的抑制（DSI）或兴奋（DSE）是内源性大麻素介导的短期可塑性的一种众所周知的形式，由突触后去极化诱导。人们普遍认为，DSI/DSE 是由通过通道划分的电压门控 Ca-2 的 Ca2+ 流入触发的。还证明 DSI/DSE 是由 2-花生四烯酰甘油 (2-AG) 介导的。然而，Ca2+如何诱导2-AG产生仍不清楚。在本研究中，我们研究了 Ca2+ 驱动的 2-AG 生产的分子机制。使用培养的海马神经元的大麻素敏感抑制性突触，我们测试了几种被认为参与 2-AG 代谢的酶抑制剂。我们测试的化学物质包括磷脂酶 C 抑制剂（U73122 和 ET-18）、二酰甘油激酶（DGK 抑制剂 1）、磷脂酸磷酸水解酶（普萘洛尔）和二酰甘油脂肪酶（DGL；RHC-80267 和四氢脂抑素 (THL)）。然而，除 THL 外，这些抑制剂均观察到不良副作用。此外，我们发现 RHC-80267 几乎不抑制由 G(q/11) 偶联受体驱动的内源性大麻素释放，这被认为是 DGL 依赖性的。相比之下，THL 在我们的测试中没有表现出任何副作用，并且被证实可以抑制 DGL 依赖性过程。使用 THL 作为 DGL 抑制剂，我们证明 DGL 参与海马 DSI 和小脑 DSE。为了测试 PLC delta 是否参与 DSI，我们检查了 PLC delta 1、delta 3 和 delta 4 敲除小鼠的海马 DSI。然而，这些基因敲除小鼠和野生型小鼠之间的 DSI 大小没有显着差异。本研究清楚地表明 DGL 是 DSI/DSE 的先决条件。产生 DG 的酶仍有待确定。 (c) 2007 Elsevier Ltd. 保留所有权利。
Depolarization-induced suppression of inhibition (DSI) or excitation (DSE) is a well-known form of endocannabinoid-mediated short-term plasticity that is induced by postsynaptic depolarization. It is generally accepted that DSI/DSE is triggered by Ca2+ influx through voltage-gated Ca-2 divided by channels. It is also demonstrated that DSI/DSE is mediated by 2-arachidonoylglycerol (2-AG). However, how Ca2+ induces 2-AG production is still unclear. In the present study, we investigated molecular mechanisms underlying the Ca2+-driven 2-AG production. Using cannabinoid-sensitive inhibitory synapses of cultured hippocampal neurons, we tested several inhibitors for enzymes that are supposed to be involved in 2-AG metabolism. The chemicals we tested include inhibitors for phospholipase C (U73122 and ET-18), diacylglycerol kinase (DGK inhibitor 1), phosphatidic acid phosphohydrolase (propranolol), and diacylglycerol lipase (DGL; RHC-80267 and tetrahydrolipstatin (THL)). However, unfavorable side effects were observed with these inhibitors, except for THL. Furthermore, we found that RHC-80267 hardly inhibited the endocannabinoid release driven by G(q/11)-coupled receptors, which is thought to be DGL-dependent. By contrast, THL exhibited no side effects as long as we tested, and was confirmed to inhibit the DGL-dependent process. Using THL as a DGL inhibitor, we demonstrated that DGL is involved in both hippocampal DSI and cerebellar DSE. To test a possible involvement of PLC delta in DSI, we examined hippocampal DSI in PLC delta 1,delta 3 and delta 4-knockout mice. However, there was no significant difference in the DSI magnitude between these knockout mice and wildtype mice. The present study clearly shows that DGL is a prerequisite for DSI/DSE. The enzymes yielding DG remain to be determined. (c) 2007 Elsevier Ltd. All rights reserved.