Regulation of NMDA receptor trafficking and gating by activity-dependent CaMKIIα phosphorylation of the GluN2A subunit.
Regulation of NMDA receptor trafficking and gating by activity-dependent CaMKIIα phosphorylation of the GluN2A subunit.
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DOI：
10.1016/j.celrep.2021.109338
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发表时间：
2021-07-06
期刊：
影响因子：
8.8
通讯作者：
Anggono V
中科院分区：
文献类型：
--
作者：
Yong XLH;Zhang L;Yang L;Chen X;Tan JZA;Yu X;Chandra M;Livingstone E;Widagdo J;Vieira MM;Roche KW;Lynch JW;Keramidas A;Collins BM;Anggono V
NMDA受体（NMDAR）依赖的Ca 2+内流支持多种形式的突触可塑性。成年前脑中的大多数突触NMDAR电流是由含GluN 2A的受体介导的，这些受体在长时程增强（LTP）过程中迅速插入突触;然而，其潜在的分子机制仍然知之甚少。在这项研究中，我们发现GluN 2A在Ser-1459被Ca 2 +/钙调蛋白依赖性激酶IIα（CaMKIIα）磷酸化，以响应甘氨酸刺激，模拟初级神经元中的LTP。Ser-1459的磷酸化促进GluN 2A与分选连接蛋白27（SNX 27）-逆转录复合物的相互作用，从而增强NMDAR的内体再循环。SNX 27或CaMKIIα功能的丧失阻断了甘氨酸诱导的神经元膜上GluN 2A-NMDAR的增加。有趣的是，Ser-1459的突变，包括罕见的S1459 G人类癫痫变异体，通过增加通道开放的持续时间来延长异突触中NMDAR介导的突触电流的衰减时间。这些发现不仅确定了Ser-1459磷酸化在调节NMDAR功能中的关键作用，而且还解释了S1459 G变体如何失调NMDAR功能。Yong等人发现，CaMKIIα对GluN 2A C端结构域中Ser-1459的活性依赖性磷酸化促进了其与SNX 27-逆转录聚合物复合物的相互作用，从而增强了突触增强过程中NMDAR的表面表达。Ser-1459的突变通过增加通道开放的持续时间来延长NMDAR介导的突触电流的衰减时间。
NMDA receptor (NMDAR)-dependent Ca2+ influx underpins multiple forms of synaptic plasticity. Most synaptic NMDAR currents in the adult forebrain are mediated by GluN2A-containing receptors, which are rapidly inserted into synapses during long-term potentiation (LTP); however, the underlying molecular mechanisms remain poorly understood. In this study, we show that GluN2A is phosphorylated at Ser-1459 by Ca2+/calmodulin-dependent kinase IIα (CaMKIIα) in response to glycine stimulation that mimics LTP in primary neurons. Phosphorylation of Ser-1459 promotes GluN2A interaction with the sorting nexin 27 (SNX27)-retromer complex, thereby enhancing the endosomal recycling of NMDARs. Loss of SNX27 or CaMKIIα function blocks the glycine-induced increase in GluN2A-NMDARs on the neuronal membrane. Interestingly, mutations of Ser-1459, including the rare S1459G human epilepsy variant, prolong the decay times of NMDAR-mediated synaptic currents in heterosynapses by increasing the duration of channel opening. These findings not only identify a critical role of Ser-1459 phosphorylation in regulating the function of NMDARs, but they also explain how the S1459G variant dysregulates NMDAR function. Yong et al. identify that activity-dependent phosphorylation of Ser-1459 in the GluN2A C-terminal domain by CaMKIIα promotes its interaction with the SNX27-retromer complex, thereby enhancing the surface expression of NMDARs during synaptic potentiation. Mutations of Ser-1459 prolong the decay times of NMDAR-mediated synaptic currents by increasing the duration of channel opening.
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