NMDA receptor-dependent regulation of dendritic spine morphology by SAP102 splice variants.
NMDA receptor-dependent regulation of dendritic spine morphology by SAP102 splice variants.
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DOI：
10.1523/jneurosci.1034-10.2011
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发表时间：
2011-01-05
期刊：
影响因子：
--
通讯作者：
Roche KW
中科院分区：
文献类型：
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作者：
Chen BS;Thomas EV;Sanz-Clemente A;Roche KW
膜相关鸟苷酸激酶（MAGUKs）是突触后密度的主要组成部分，在突触组织和可塑性中起重要作用。大多数兴奋性突触位于树突棘上，树突棘是动态结构，在突触形成和可塑性过程中经历形态变化。突触相关蛋白102 （SAP102）是一种在发育早期高表达的MAGUK，并在突触发生过程中介导受体转运。人类SAP102的突变导致智力迟钝，这通常伴随着树突棘的异常。然而，SAP102在调节突触形成或脊柱形态中的作用知之甚少。我们现在发现SAP102在n端结构域含有一个新的NMDA受体结合位点，这是NR2B亚基特异性的。SAP102与NR2B的相互作用与PDZ结构域无关，受SAP102的选择性剪接调控。我们发现，具有n端插入的SAP102在mRNA和蛋白质水平上都受到发育调节。此外，SAP102的表达增加了突触的形成。此外，SAP102的选择性剪接调节树突棘的形态。含有n端插入的SAP102促进树突棘的延长，并优先促进长棘突触的形成，而shRNA敲低相同的SAP102剪接变体会导致脊柱收缩。最后，阻断NMDA受体活性可防止SAP102 n端剪接变体诱导的脊柱延长。因此，我们的数据提供了SAP102将NMDA受体激活与脊柱形态改变联系起来的第一个证据。
Membrane associated guanylate kinases (MAGUKs) are major components of the postsynaptic density and play important roles in synaptic organization and plasticity. Most excitatory synapses are located on dendritic spines, which are dynamic structures that undergo morphological changes during synapse formation and plasticity. Synapse-associated protein 102 (SAP102) is a MAGUK that is highly expressed early in development and mediates receptor trafficking during synaptogenesis. Mutations in human SAP102 cause mental retardation, which is often accompanied with abnormalities in dendritic spines. However, little is known about the role of SAP102 in regulating synapse formation or spine morphology. We now find that SAP102 contains a novel NMDA receptor binding site in the N-terminal domain, which is specific for the NR2B subunit. The interaction between SAP102 and NR2B is PDZ domain-independent and is regulated by alternative splicing of SAP102. We show that SAP102 that possesses an N-terminal insert is developmentally regulated at both mRNA and protein levels. In addition, expression of SAP102 increases synapse formation. Furthermore, the alternative splicing of SAP102 regulates dendritic spine morphology. SAP102 containing the N-terminal insert promotes lengthening of dendritic spines and preferentially promotes the formation of synapses at long spines, whereas an shRNA knockdown of the same SAP102 splice variant causes spine shrinkage. Finally, blocking NMDA receptor activity prevents the spine lengthening induced by the N-terminal splice variant of SAP102. Thus, our data provide the first evidence that SAP102 links NMDA receptor activation to alterations in spine morphology.