Role of the CaMKII/NMDA receptor complex in the maintenance of synaptic strength.
Role of the CaMKII/NMDA receptor complex in the maintenance of synaptic strength.
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DOI：
10.1523/jneurosci.1250-11.2011
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发表时间：
2011-06-22
期刊：
影响因子：
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通讯作者：
Lisman J
中科院分区：
文献类型：
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作者：
Sanhueza M;Fernandez-Villalobos G;Stein IS;Kasumova G;Zhang P;Bayer KU;Otmakhov N;Hell JW;Lisman J
在长时程增强（LTP）过程中，突触经历突触强度的稳定变化。维持强度的分子记忆过程还没有被确定。一种假设是由Ca 2 +/钙调蛋白依赖性蛋白激酶II（CaMKII）和NMDA型谷氨酸受体（NMDAR）形成的复合物是突触处的分子记忆。要建立一个分子作为分子记忆，它必须表明，干扰分子产生持久逆转的LTP。我们使用CN类肽抑制CaMKII结合NR 2B亚基在体外测试这一预测在大鼠海马切片。我们发现CN肽可以逆转饱和的LTP，从而诱导额外的LTP。该肽还产生了持续减少基础传输。然后，我们测试了CN化合物是否真的影响活细胞中的CaMKII结合。应用CN肽切片培养物减少的量的CaMKII集中在脊柱，与离域的激酶从结合伴侣在脊柱。为了更特异地测定CaMK II与NMDAR的结合，我们使用了免疫共沉淀法。我们发现CN肽仅在破坏CaMKII/NMDAR复合物所需的浓度下降低突触强度，但在足以抑制CaMKII活性的较低浓度下不降低突触强度。重要的是，复合物的减少和突触强度的降低在去除抑制剂后仍然存在。这些结果支持了CaMKII/NMDAR复合物具有开关样性质的假设，该开关样性质在维持突触强度中是重要的。
During long-term potentiation (LTP), synapses undergo stable changes in synaptic strength. The molecular memory processes that maintain strength have not been identified. One hypothesis is that the complex formed by the Ca2+/Calmodulin -dependent protein kinase II (CaMKII) and the NMDA-type glutamate receptor (NMDAR) is a molecular memory at the synapse. To establish a molecule as a molecular memory, it must be shown that interfering with the molecule produces a persistent reversal of LTP. We used the CN class of peptides that inhibit CaMKII binding to the NR2B subunit in vitro to test this prediction in rat hippocampal slices. We found that CN peptides can reverse saturated LTP, allowing additional LTP to be induced. The peptide also produced a persistent reduction in basal transmission. We then tested whether CN compounds actually affect CaMKII binding in living cells. Application of CN peptide to slice cultures reduced the amount of CaMKII concentrated in spines, consistent with delocalization of the kinase from a binding partner in the spine. To more specifically assay the binding of CaMKII to the NMDAR, we used coimmunoprecipitation methods. We found that CN peptide decreased synaptic strength only at concentrations necessary to disrupt the CaMKII/NMDAR complex, but not at lower concentrations sufficient to inhibit CaMKII activity. Importantly, both the reduction of the complex and the reduction of synaptic strength persisted after removal of the inhibitor. These results support the hypothesis that the CaMKII/NMDAR complex has switch-like properties that are important in the maintenance of synaptic strength.