Co-agonists differentially tune GluN2B-NMDA receptor trafficking at hippocampal synapses
Co-agonists differentially tune GluN2B-NMDA receptor trafficking at hippocampal synapses
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DOI：
10.7554/elife.25492
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发表时间：
2017-06-09
期刊：
影响因子：
7.7
通讯作者：
Groc, Laurent
中科院分区：
文献类型：
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作者：
Ferreira, Joana S.;Papouin, Thomas;Groc, Laurent
突触NMDA受体（NMDAR）的亚基组成，如GluN 2A和GluN 2B受体的相对含量，对谷氨酸突触传递有重要影响。受体共激动剂，甘氨酸和D-丝氨酸，已经有趣地出现作为受体运输的潜在调节剂，除了它们的激活要求。使用单分子成像，生物化学和电生理学的组合，我们表明，甘氨酸和D-丝氨酸在大鼠海马神经元突触的相对可用性调节NMDAR亚型的运输和突触内容。离体和体外共激动剂水平的急性操作揭示了D-丝氨酸通过需要PDZ结合支架伴侣的过程在突触处改变GluN 2B-NMDAR的膜动力学和含量，但不改变GluN 2A-NMDAR。此外，使用基于FRET的FLIM方法，我们证明，D-丝氨酸迅速诱导GluN 1亚基胞内C-末端结构域的构象变化。我们的数据共同支持细胞外微环境调节突触NMDAR信号传导的观点。
The subunit composition of synaptic NMDA receptors (NMDAR), such as the relative content of GluN2A- and GluN2B-containing receptors, greatly influences the glutamate synaptic transmission. Receptor co-agonists, glycine and D-serine, have intriguingly emerged as potential regulators of the receptor trafficking in addition to their requirement for its activation. Using a combination of single-molecule imaging, biochemistry and electrophysiology, we show that glycine and D-serine relative availability at rat hippocampal glutamatergic synapses regulate the trafficking and synaptic content of NMDAR subtypes. Acute manipulations of co-agonist levels, both ex vivo and in vitro, unveil that D-serine alter the membrane dynamics and content of GluN2B-NMDAR, but not GluN2A-NMDAR, at synapses through a process requiring PDZ binding scaffold partners. In addition, using FRET-based FLIM approach, we demonstrate that D-serine rapidly induces a conformational change of the GluN1 subunit intracellular C-terminus domain. Together our data fuels the view that the extracellular microenvironment regulates synaptic NMDAR signaling.