NMDA 受体组成的发育转变独立于 GluN2 亚基特异性 GluN2 C 末端序列进行。
The Developmental Shift of NMDA Receptor Composition Proceeds Independently of GluN2 Subunit-Specific GluN2 C-Terminal Sequences.
机构信息
Centre for Discovery Brain Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK; Simons Initiative for the Developing Brain, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK; UK Dementia Research Institute at the University of Edinburgh, Chancellor's Building, Edinburgh Medical School, Edinburgh EH16 4SB, UK.
School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute and Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland; Florey Institute of Neuroscience and Mental Health, Melbourne Brain Centre, University of Melbourne, Parkville, VIC, Australia.
出版信息
Cell Rep. 2018 Oct 23;25(4):841-851.e4. doi: 10.1016/j.celrep.2018.09.089.
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.
GluN2 亚型（2A 与 2B）决定了前脑 NMDA 受体（NMDAR）的生物物理特性和信号转导。在发育过程中，GluN2A 被整合到以前由 GluN2B 主导的 NMDAR 中。这种“转换”据推测是由 GluN2 细胞质 C 末端结构域（CTD）的独特特征驱动的，包括 GluN2B 中独特的 CaMKII 相互作用位点，该位点驱动其从突触中去除。然而，这些模型在内源性 NMDAR 中仍未得到验证。我们表明，尽管突变内源性 GluN2B CaMKII 位点对 GluN2B CTD 磷酸化有次要影响，但 NMDAR 组成的发育变化仍正常发生，并且可塑性和突触发生的测量值不受影响。此外，在 GluN2A CTD 被 GluN2B CTD 取代的小鼠中，转换正常进行，并且在 GluN2B 水平没有明显下降的情况下开始，但 GluN2A 半不足会使其受损。因此，GluN2A 的表达水平，而不是 GluN2 亚型特异性 CTD 驱动的事件，是 NMDAR 组成发育转换的主要因素。
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