Blockade of 2-Arachidonoylglycerol Hydrolysis by Selective Monoacylglycerol Lipase Inhibitor 4-Nitrophenyl 4-(Dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate (JZL184) Enhances Retrograde Endocannabinoid Signaling
Blockade of 2-Arachidonoylglycerol Hydrolysis by Selective Monoacylglycerol Lipase Inhibitor 4-Nitrophenyl 4-(Dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate (JZL184) Enhances Retrograde Endocannabinoid Signaling
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DOI：
10.1124/jpet.109.158162
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发表时间：
2009-11-01
影响因子：
3.5
通讯作者：
Liu, Qing-song
中科院分区：
文献类型：
--
作者：
Pan, Bin;Wang, Wei;Liu, Qing-song
内源性大麻素（eCB）信号介导去极化诱导的兴奋抑制（DSE）和抑制（DSI），这是逆行突触抑制的两种主要形式。n -花生四烯酰基乙醇胺（AEA）和2-花生四烯酰基甘油（2-AG）分别被脂肪酸酰胺水解酶（FAAH）和单酰基甘油脂肪酶（MAGL）降解。选择性阻断FAAH和MAGL对于确定eCBs在DSE/DSI中的作用以及了解它们的作用是如何被调节的至关重要。4- nitrophenyl 4-（dibenzo[d][1,3]dioxol-5-yl（羟基）甲基）哌啶-1-carboxylate （JZL184）是一种高选择性的MAGL抑制剂，可增加小鼠脑内2-AG浓度而不增加AEA浓度。本研究报告JZL184延长了小脑浦肯野神经元的DSE和海马CA1锥体神经元的DSI。JZL184对DSE/DSI的影响由非选择性MAGL抑制剂花生四烯基氟膦酸甲酯模拟。相比之下，选择性FAAH抑制剂环己基氨基甲酸3′-羰基联苯-3-基酯（URB597）和FAAH敲除对DSE/DSI均无显著影响。JZL184对小鼠神经元DSE/ DSI的增强作用强于对大鼠神经元的增强作用。后者的发现与生化研究一致，表明JZL184对小鼠MAGL的抑制作用强于大鼠MAGL。这些结果表明，MAGL对2-AG的降解是决定DSE/DSI时间进程的限速步骤，JZL184是研究2-AG介导的信号传导的有用工具。
Endocannabinoid (eCB) signaling mediates depolarization-induced suppression of excitation (DSE) and inhibition (DSI), two prominent forms of retrograde synaptic depression. N-Arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG), two known eCBs, are degraded by fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively. Selective blockade of FAAH and MAGL is critical for determining the roles of the eCBs in DSE/DSI and understanding how their action is regulated. 4-Nitrophenyl 4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate (JZL184) is a recently developed, highly selective, and potent MAGL inhibitor that increases 2-AG but not AEA concentrations in mouse brain. Here, we report that JZL184 prolongs DSE in Purkinje neurons in cerebellar slices and DSI in CA1 pyramidal neurons in hippocampal slices. The effect of JZL184 on DSE/DSI is mimicked by the nonselective MAGL inhibitor methyl arachidonyl fluorophosphonate. In contrast, neither the selective FAAH inhibitor cyclohexylcarbamic acid 3'-carbomoylbiphenyl-3-yl ester (URB597) nor FAAH knockout has a significant effect on DSE/DSI. JZL184 produces greater enhancement of DSE/ DSI in mouse neurons than that in rat neurons. The latter finding is consistent with biochemical studies showing that JZL184 is more potent in inhibiting mouse MAGL than rat MAGL. These results indicate that the degradation of 2-AG by MAGL is the rate-limiting step that determines the time course of DSE/DSI and that JZL184 is a useful tool for the study of 2-AG-mediated signaling.