Synaptic and Extrasynaptic NMDA Receptors Are Gated by Different Endogenous Coagonists
Synaptic and Extrasynaptic NMDA Receptors Are Gated by Different Endogenous Coagonists
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DOI：
10.1016/j.cell.2012.06.029
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发表时间：
2012-08-03
期刊：
影响因子：
64.5
通讯作者：
Oliet, Stephane H. R.
中科院分区：
文献类型：
--
作者：
Papouin, Thomas;Ladepeche, Laurent;Oliet, Stephane H. R.
N-甲基-D-天冬氨酸受体（NMDAR）位于神经元细胞膜的突触和突触外位置，在那里它们被认为介导不同的生理和病理过程。NMDAR的激活需要谷氨酸和凝血剂，其性质和对NMDAR生理学的影响仍然难以捉摸。我们报告，突触和突触外NMDAR门控不同的内源性凝血因子，D-丝氨酸和甘氨酸，分别。促凝剂的区域化可用性与突触NMDAR对D-丝氨酸和突触外NMDAR对甘氨酸的优先亲和力相匹配。此外，甘氨酸和D-丝氨酸以亚基依赖性方式抑制NMDAR表面运输，这可能影响NMDAR的亚细胞定位。利用这种凝血分离，我们证明了长时程增强和NMDA诱导的神经毒性依赖于突触NMDAR。相反，长期抑郁需要突触和突触外受体。我们的观察提供了关键的见解NMDARs的操作模式，强调突触和突触外NMDARs在脑生理功能的区别。
N-methyl-D-aspartate receptors (NMDARs) are located in neuronal cell membranes at synaptic and extrasynaptic locations, where they are believed to mediate distinct physiological and pathological processes. Activation of NMDARs requires glutamate and a coagonist whose nature and impact on NMDAR physiology remain elusive. We report that synaptic and extrasynaptic NMDARs are gated by different endogenous coagonists, D-serine and glycine, respectively. The regionalized availability of the coagonists matches the preferential affinity of synaptic NMDARs for D-serine and extrasynaptic NMDARs for glycine. Furthermore, glycine and D-serine inhibit NMDAR surface trafficking in a subunit-dependent manner, which is likely to influence NMDARs subcellular location. Taking advantage of this coagonist segregation, we demonstrate that long-term potentiation and NMDA-induced neurotoxicity rely on synaptic NMDARs only. Conversely, long-term depression requires both synaptic and extrasynaptic receptors. Our observations provide key insights into the operating mode of NMDARs, emphasizing functional distinctions between synaptic and extrasynaptic NMDARs in brain physiology.