Hippocampal synaptic plasticity involves competition between Ca2+/calmodulin-dependent protein kinase II and postsynaptic density 95 for binding to the NR2A subunit of the NMDA receptor
Hippocampal synaptic plasticity involves competition between Ca2+/calmodulin-dependent protein kinase II and postsynaptic density 95 for binding to the NR2A subunit of the NMDA receptor
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DOI：
10.1523/jneurosci.21-05-01501.2001
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发表时间：
2001-03-01
影响因子：
5.3
通讯作者：
Di Luca, M
中科院分区：
文献类型：
--
作者：
Gardoni, F;Schrama, LH;Di Luca, M
NMDA受体、Ca2+/钙调素依赖性蛋白激酶II （α CaMKII）和突触后密度95 （PSD-95）是PSD部分的三个主要组成部分。α - CaMKII和PSD-95均可结合NMDA受体复合物的NR2亚基。然而，靶向NMDA受体亚基的性质和机制尚不完全清楚。在这里，我们报道了c端NR2A（S1389-V1464）序列足以保证天然和重组α CaMKII与PSD-95的关联。PSD-95（54-256）能够与天然和重组α CaMKII与NR2A c -尾的结合竞争。因此，α CaMKII（1-325）与天然PSD-95和天然激酶本身竞争与NR2A的结合。此外，NR2A独特的CaMKII磷酸化位点Ser/Ala1289和Ser/Asp1289点突变对天然α CaMKII和PSD-95与NR2A c尾的结合没有显著影响。最后，α - CaMKII和PSD-95与NR2A c尾之间的关联-解离可以通过药理工具或长期增强诱导的NMDA受体激活来显著调节，这强调了NMDA受体、α - CaMKII和PSD-95在海马突触可塑性中的动态和相互作用的重要性。
NMDA receptor, Ca2+/calmodulin-dependent protein kinase II (alpha CaMKII), and postsynaptic density 95 (PSD-95) are three major components of the PSD fraction. Both alpha CaMKII and PSD-95 have been shown previously to bind NR2 subunits of the NMDA receptor complex. The nature and mechanisms of targeting to the NMDA receptor subunits are, however, not completely understood. Here we report that the C-terminal NR2A(S1389-V1464) sequence was sufficient to guarantee the association of both native and recombinant alpha CaMKII and PSD-95. PSD-95(54-256) was able to compete with the binding of both native and recombinant alpha CaMKII to the NR2A C-tail. Accordingly, alpha CaMKII(1-325) competes with both the native PSD-95 and the native kinase itself for the binding to NR2A. In addition, Ser/Ala1289 and Ser/Asp1289 point mutations on the unique CaMKII phosphosite of NR2A did not significantly influence the binding of native alpha CaMKII and PSD-95 to the NR2A C-tail. Finally, the association-dissociation of alpha CaMKII and PSD-95 to and from the NR2A C-tail was significantly modulated by activation of NMDA receptor achieved by either pharmacological tools or long-term potentiation induction, underlining the importance of dynamic and reciprocal interactions of NMDA receptor, alpha CaMKII, and PSD-95 in hippocampal synaptic plasticity.