Neuronal Protease-Activated Receptor 1 Drives Synaptic Retrograde Signaling Mediated by the Endocannabinoid 2-Arachidonoylglycerol
Neuronal Protease-Activated Receptor 1 Drives Synaptic Retrograde Signaling Mediated by the Endocannabinoid 2-Arachidonoylglycerol
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DOI：
10.1523/jneurosci.6000-10.2011
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发表时间：
2011-02-23
影响因子：
5.3
通讯作者：
Kano, Masanobu
中科院分区：
文献类型：
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作者：
Hashimotodani, Yuki;Ohno-Shosaku, Takako;Kano, Masanobu
蛋白酶激活受体1 （PAR1）是g蛋白偶联受体的成员，可被丝氨酸蛋白酶水解激活。最近的研究表明，PAR1对包括学习和记忆在内的大脑功能有明确的贡献。然而，PAR1激活影响神经元活动的细胞机制尚不清楚。在这里，我们发现PAR1激活驱动逆行内源性大麻素信号传导，从而调节突触传递。在培养的大鼠海马神经元中，凝血酶或PAR1特异性肽激动剂激活PAR1可短暂抑制大麻素敏感突触的抑制传递，但不抑制大麻素不敏感突触的抑制传递。par1诱导的突触传递抑制伴随着配对脉冲比的增加，并被大麻素CB1受体拮抗剂阻断。par1诱导的抑制被突触后二酰基甘油脂肪酶（DGL）的药理抑制阻断，DGL是主要内源性大麻素2-花生四烯醇甘油（2-AG）生物合成的关键酶，并且在缺乏DGL α亚型的敲除小鼠中不存在。PAR1诱导的IPSC抑制在代谢性谷氨酸受体的阻断下保持完整，并且在很大程度上抵抗PAR1激活后阻断胶质细胞Ca2+升高的治疗，这排除了胶质PAR1在IPSC抑制中的主要贡献。我们得出结论，神经元PAR1的激活触发了2-AG介导的逆行信号传导，其激活突触前CB1受体并抑制海马抑制性突触的递质释放。
Protease-activated receptor 1 (PAR1) is a member of the G-protein coupled receptors that are proteolytically activated by serine proteases. Recent studies suggest a definite contribution of PAR1 to brain functions, including learning and memory. However, cellular mechanisms by which PAR1 activation influences neuronal activity are not well understood. Here we show that PAR1 activation drives retrograde endocannabinoid signaling and thereby regulates synaptic transmission. In cultured hippocampal neurons from rat, PAR1 activation by thrombin or PAR1-specific peptide agonists transiently suppressed inhibitory transmission at cannabinoid-sensitive, but not cannabinoid-insensitive, synapses. The PAR1-induced suppression of synaptic transmission was accompanied by an increase in paired-pulse ratio, and was blocked by a cannabinoid CB1 receptor antagonist. The PAR1-induced suppression was blocked by pharmacological inhibition of postsynaptic diacylglycerol lipase (DGL), a key enzyme for biosynthesis of the major endocannabinoid 2-arachidonoylglycerol (2-AG), and was absent in knock-out mice lacking the alpha isoform of DGL. The PAR1-induced IPSC suppression remained intact under the blockade of metabotropic glutamate receptors and was largely resistant to the treatment that blocked Ca2+ elevation in glial cells following PAR1 activation, which excludes the major contribution of glial PAR1 in IPSC suppression. We conclude that activation of neuronal PAR1 triggers retrograde signaling mediated by 2-AG, which activates presynaptic CB1 receptors and suppresses transmitter release at hippocampal inhibitory synapses.