Unmasking GluN1/GluN3A excitatory glycine NMDA receptors.
Unmasking GluN1/GluN3A excitatory glycine NMDA receptors.
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DOI：
10.1038/s41467-018-07236-4
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发表时间：
2018-11-13
影响因子：
16.6
通讯作者：
Paoletti P
中科院分区：
文献类型：
--
作者：
Grand T;Abi Gerges S;David M;Diana MA;Paoletti P
GluN 3A和GluN 3B是属于NMDA受体（NMDAR）家族的甘氨酸结合亚基，其可以与GluN 1亚基组装以形成单独由甘氨酸激活的非常规受体。GluN 1/GluN 3 NMDAR的功能表征一直很困难。在这里，我们发现了两种对GluN 1/GluN 3A受体具有变革性质的方式。首先，我们确定了一种化合物，CGP-78608，它大大增强了GluN 1/GluN 3A的反应，将小而快速的脱敏电流转化为大而稳定的反应。其次，我们发现，内源性GluN 3A二硫键赋予GluN 1/GluN 3A受体不同的氧化还原调节，深刻影响激动剂的敏感性和门控动力学。在还原条件下，环境甘氨酸足以产生紧张性受体激活。最后，使用CGP-78608对P8-P12小鼠海马切片，我们证明兴奋性甘氨酸GluN 1/GluN 3A NMDAR在天然神经元中功能性表达，至少在幼年脑中。我们的工作为探索大脑功能和发育中的兴奋性甘氨酸受体开辟了新的视角。兴奋性甘氨酸GluN 1/GluN 3A受体是难以研究的非典型NMDAR。在这里，作者确定了这些受体的新特性，包括GluN 1拮抗剂CGP-78608的增强作用，该拮抗剂允许检测幼年大脑中的功能性GluN 1/GluN 3A受体。
GluN3A and GluN3B are glycine-binding subunits belonging to the NMDA receptor (NMDAR) family that can assemble with the GluN1 subunit to form unconventional receptors activated by glycine alone. Functional characterization of GluN1/GluN3 NMDARs has been difficult. Here, we uncover two modalities that have transformative properties on GluN1/GluN3A receptors. First, we identify a compound, CGP-78608, which greatly enhances GluN1/GluN3A responses, converting small and rapidly desensitizing currents into large and stable responses. Second, we show that an endogenous GluN3A disulfide bond endows GluN1/GluN3A receptors with distinct redox modulation, profoundly affecting agonist sensitivity and gating kinetics. Under reducing conditions, ambient glycine is sufficient to generate tonic receptor activation. Finally, using CGP-78608 on P8-P12 mouse hippocampal slices, we demonstrate that excitatory glycine GluN1/GluN3A NMDARs are functionally expressed in native neurons, at least in the juvenile brain. Our work opens new perspectives on the exploration of excitatory glycine receptors in brain function and development. Excitatory glycine GluN1/GluN3A receptors are atypical NMDARs that have been difficult to study. Here the authors identify new properties of these receptors, including potentiation by the GluN1 antagonist CGP-78608 that allows detection of functional GluN1/GluN3A receptors in the juvenile brain.
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影响因子：
16.2
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通讯作者：
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