Soluble Ectodomain of Neuroligin 1 Decreases Synaptic Activity by Activating Metabotropic Glutamate Receptor 2.
Soluble Ectodomain of Neuroligin 1 Decreases Synaptic Activity by Activating Metabotropic Glutamate Receptor 2.
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DOI：
10.3389/fnmol.2017.00116
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发表时间：
2017
影响因子：
4.8
通讯作者：
Owczarek S
中科院分区：
文献类型：
--
作者：
Gjørlund MD;Carlsen EMM;Kønig AB;Dmytrieva O;Petersen AV;Jacobsen J;Berezin V;Perrier JF;Owczarek S
突触细胞粘附分子是神经元活性依赖性蛋白水解的重要靶点。突触后神经配素（NL）与突触前神经毒素（NX）形成跨突触复合物。NXs和NLs均通过金属蛋白酶以活性依赖性方式从细胞表面切割，释放可溶性细胞外片段和膜系连的C末端片段。NL1的裂解抑制突触传递，但其发生机制尚不清楚。代谢型谷氨酸受体2（mGluR2）主要位于突触前末梢的外周，在那里它们抑制环磷酸腺苷（cAMP）的形成，从而抑制谷氨酸的释放并减少突触传递。在本研究中，我们发现NL1的可溶性胞外域结合并激活神经元和异源细胞中的mGluR2，导致cAMP形成减少。在小鼠海马的切片制备中，NL1抑制了投射到CA3锥体神经元的苔藓纤维释放谷氨酸。NL1的突触前效应在mGluR2的选择性拮抗剂的存在下被废除。因此，我们的数据表明，NL1的可溶性细胞外结构域功能上与mGluR2相互作用，从而降低突触强度。
Synaptic cell adhesion molecules represent important targets for neuronal activity-dependent proteolysis. Postsynaptic neuroligins (NLs) form trans-synaptic complexes with presynaptic neurexins (NXs). Both NXs and NLs are cleaved from the cell surface by metalloproteases in an activity-dependent manner, releasing a soluble extracellular fragment and membrane-tethered C-terminal fragment. The cleavage of NL1 depresses synaptic transmission, but the mechanism by which this occurs is unknown. Metabotropic glutamate receptor 2 (mGluR2) are located primarily at the periphery of presynaptic terminals, where they inhibit the formation of cyclic adenosine monophosphate (cAMP) and consequently suppress the release of glutamate and decrease synaptic transmission. In the present study, we found that the soluble ectodomain of NL1 binds to and activates mGluR2 in both neurons and heterologous cells, resulting in a decrease in cAMP formation. In a slice preparation from the hippocampus of mice, NL1 inhibited the release of glutamate from mossy fibers that project to CA3 pyramidal neurons. The presynaptic effect of NL1 was abolished in the presence of a selective antagonist for mGluR2. Thus, our data suggest that the soluble extracellular domain of NL1 functionally interacts with mGluR2 and thereby decreases synaptic strength.