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首页> 外文期刊>Neuron >Activity-dependent mRNA splicing controls ER export and synaptic delivery of NMDA receptors.
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Activity-dependent mRNA splicing controls ER export and synaptic delivery of NMDA receptors.

机译：依赖于活性的mRNA剪接控制ER出口和NMDA受体的突触传递。

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摘要

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.
机译：NMDA受体（NMDARs）的活动依赖性靶向是突触形成和可塑性的关键特征。尽管已经确定了谷氨酸受体快速运输的机制，但突触NMDARs的长期积累或丧失的分子事件仍然不清楚。在这里，我们证明了活动通过调节内质网（ER）的正向运输来控制NMDAR突触积累。 ER的输出通过NR1亚基的可变剪接的C2'结构域加速，并通过C2剪接盒而减慢。在C2 / C2'位点的这种mRNA剪接事件是活性依赖性的，其中C2'变体主要受活性阻断，而C2变体则具有丰富的活性。转换为C2'通过将新生的NMDAR通过C2'中的缬氨酸基序与COPII涂层结合来增强新生NMDAR向ER出口位点的募集来加速NMDAR向前运输。这些结果定义了谷氨酸受体的活性依赖靶向的新型途径，在兴奋性突触修饰过程中提供了活性，mRNA剪接和膜运输之间的意想不到的机制联系。

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