The Developmental Shift of NMDA Receptor Composition Proceeds Independently of GluN2 Subunit-Specific GluN2 C-Terminal Sequences.
The Developmental Shift of NMDA Receptor Composition Proceeds Independently of GluN2 Subunit-Specific GluN2 C-Terminal Sequences.
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DOI：
10.1016/j.celrep.2018.09.089
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发表时间：
2018-10-23
期刊：
影响因子：
8.8
通讯作者：
Komiyama NH
中科院分区：
文献类型：
--
作者：
McKay S;Ryan TJ;McQueen J;Indersmitten T;Marwick KFM;Hasel P;Kopanitsa MV;Baxter PS;Martel MA;Kind PC;Wyllie DJA;O'Dell TJ;Grant SGN;Hardingham GE;Komiyama NH
GluN 2亚型（2A与2B）决定生物物理特性和前脑NMDA受体（NMDAR）的信号传导。在发育过程中，GluN 2A被整合到以前GluN 2B主导的NMDAR中。这种“开关”被认为是由GluN 2胞质C-末端结构域（CTD）的独特特征驱动的，包括GluN 2B中驱动从突触中去除的独特CaMKII相互作用位点。然而，这些模型在内源性NMDAR的背景下仍然未经检验。我们发现，虽然突变的内源性GluN 2B CaMKII网站有二次影响GluN 2B CTD磷酸化，NMDAR组成的发育变化正常发生和可塑性和突触发生的措施不受影响。此外，开关在具有GluN 2A CTD被GluN 2B CTD取代的小鼠中正常进行，并且在GluN 2B水平没有可观察到的下降的情况下开始，但受到GluN 2A单倍不足的损害。因此，GluN 2A表达水平，而不是GluN 2亚型特异性CTD驱动的事件，是NMDAR组成中发育转换的首要因素。突变GluN 2B CaMKII位点影响其C-末端结构域的磷酸化NMDAR组成和突触发生的发育变化正常发生NMDAR组成的变化不需要不同的GluN 2 C-末端结构域NMDAR组成的发育变化主要对GluN 2A水平敏感前脑神经元发育的一个重要里程碑是NMDA受体组成的转换：GluN 2A被并入先前GluN 2B主导的NMDAR中。McKay et al.发现，与早期提出的模型相反，开关不需要GluN 2A和GluN 2B拥有不同的C-末端结构域序列。
The GluN2 subtype (2A versus 2B) determines biophysical properties and signaling of forebrain NMDA receptors (NMDARs). During development, GluN2A becomes incorporated into previously GluN2B-dominated NMDARs. This “switch” is proposed to be driven by distinct features of GluN2 cytoplasmic C-terminal domains (CTDs), including a unique CaMKII interaction site in GluN2B that drives removal from the synapse. However, these models remain untested in the context of endogenous NMDARs. We show that, although mutating the endogenous GluN2B CaMKII site has secondary effects on GluN2B CTD phosphorylation, the developmental changes in NMDAR composition occur normally and measures of plasticity and synaptogenesis are unaffected. Moreover, the switch proceeds normally in mice that have the GluN2A CTD replaced by that of GluN2B and commences without an observable decline in GluN2B levels but is impaired by GluN2A haploinsufficiency. Thus, GluN2A expression levels, and not GluN2 subtype-specific CTD-driven events, are the overriding factor in the developmental switch in NMDAR composition. Mutating the GluN2B CaMKII site affects phosphorylation of its C-terminal domain The developmental changes in NMDAR composition and synaptogenesis occur normally Changes in NMDAR composition do not require distinct GluN2 C-terminal domains Developmental changes in NMDAR composition are primarily sensitive to GluN2A levels An important milestone in forebrain neuronal development is the switch in composition of the NMDA receptor: GluN2A becomes incorporated into previously GluN2B-dominated NMDARs. Using knockin mice, McKay et al. find that, contrary to earlier proposed models, the switch does not require GluN2A and GluN2B to possess distinct C-terminal domain sequences.
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