Activity-dependent mRNA splicing controls ER export and synaptic delivery of NMDA receptors
Activity-dependent mRNA splicing controls ER export and synaptic delivery of NMDA receptors
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DOI：
10.1016/s0896-6273(03)00676-7
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发表时间：
2003-10-30
期刊：
影响因子：
16.2
通讯作者：
Ehlers, MD
中科院分区：
文献类型：
--
作者：
Mu, YY;Otsuka, T;Ehlers, MD
NMDA受体（NMDAR）的活性依赖性靶向是突触形成和可塑性的关键特征。虽然谷氨酸受体的快速运输机制已被确定，但突触NMDAR慢性积累或丢失的分子事件仍不清楚。在这里，我们表明，活动控制NMDAR突触积累，通过调节前向贩运在内质网（ER）。ER输出通过NR 1亚基的选择性剪接的C2'结构域加速，并通过C2剪接盒减慢。在C2/C2'位点的这种mRNA剪接事件是活性依赖性的，其中C2'变体在活性阻断时占优势，而C2变体丰富且活性增加。向C2'的转变通过C2'内的二缬氨酸基序与COPII外套的结合来增强新生NMDAR向ER出口位点的募集，从而加速NMDAR的向前运输。这些结果定义了一种新的途径，其基础是谷氨酸受体的活性依赖性靶向，提供了兴奋性突触修饰期间活性、mRNA剪接和膜运输之间的意外机制联系。
Activity-dependent targeting of NMDA receptors (NMDARs) is a key feature of synapse formation and plasticity. Although mechanisms for rapid trafficking of glutamate receptors have been identified, the molecular events underlying chronic accumulation or loss of synaptic NMDARs have remained unclear. Here we demonstrate that activity controls NMDAR synaptic accumulation by regulating forward trafficking at the endoplasmic reticulum (ER). ER export is accelerated by the alternatively spliced C2' domain of the NR1 subunit and slowed by the C2 splice cassette. This mRNA splicing event at the C2/C2' site is activity dependent, with C2' variants predominating upon activity blockade and C2 variants abundant with increased activity. The switch to C2' accelerates NMDAR forward trafficking by enhancing recruitment of nascent NMDARs to ER exit sites via binding of a divaline motif within C2' to COPII coats. These results define a novel pathway underlying activity-dependent targeting of glutamate receptors, providing an unexpected mechanistic link between activity, mRNA splicing, and membrane trafficking during excitatory synapse modification.