Atkins Coleen M, Davare Monika A, Oh Michael C, Derkach Victor, Soderling Thomas R
Vollum Institute, Oregon Health and Science University, Portland, Oregon 97239, USA.
J Neurosci. 2005 Jun 8;25(23):5604-10. doi: 10.1523/JNEUROSCI.5051-04.2005.
Induction of hippocampal long-term potentiation (LTP) requires activation of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), whereas maintenance of LTP additionally requires protein synthesis. We recently reported that CaMKII stimulates protein synthesis in depolarized hippocampal neurons through phosphorylation of the mRNA translation factor cytoplasmic polyadenylation element-binding protein (CPEB), and this phosphorylation is rapidly reversed by protein phosphatase 1 (PP1). Protein synthesis-dependent late-phase LTP (L-LTP) in the hippocampus requires calcium influx through the NMDA-type glutamate receptor (NMDA-R) to activate CaMKII as well as concomitant inhibition of PP1 mediated by protein kinase A. Therefore, we investigated the regulation of CPEB phosphorylation during L-LTP. Pharmacological stimulation of the NMDA-R in hippocampal slices to produce chemical long-term depression induced a brief dephosphorylation of CPEB. Modest LTP induction (once at 100 Hz), which induces a protein synthesis-independent early-phase LTP (E-LTP), resulted in a transient phosphorylation of CPEB. However, stronger stimulation (four times at 100 Hz), known to induce protein synthesis-dependent L-LTP, elicited a prolonged phosphorylation of CPEB. Furthermore, CPEB phosphorylation correlated with phosphorylation of PP1 inhibitor dopamine- and cAMP-regulated phosphoprotein, a known substrate for protein kinase A. These results evoke the hypothesis that bidirectional regulation of CPEB phosphorylation by CaMKII and protein phosphatases may serve as a mechanism to convert E-LTP into protein synthesis-dependent L-LTP by stimulating protein synthesis and thereby stabilizing synaptic enhancement.
海马体长期增强效应（LTP）的诱导需要激活钙/钙调蛋白依赖性蛋白激酶II（CaMKII），而LTP的维持还需要蛋白质合成。我们最近报道，CaMKII通过磷酸化mRNA翻译因子细胞质聚腺苷酸化元件结合蛋白（CPEB）来刺激去极化海马神经元中的蛋白质合成，并且这种磷酸化会被蛋白磷酸酶1（PP1）迅速逆转。海马体中依赖蛋白质合成的晚期LTP（L-LTP）需要通过NMDA型谷氨酸受体（NMDA-R）的钙内流来激活CaMKII，以及蛋白激酶A介导的对PP1的同时抑制。因此，我们研究了L-LTP过程中CPEB磷酸化的调节。对海马切片中的NMDA-R进行药理学刺激以产生化学性长期抑制，会导致CPEB短暂去磷酸化。适度的LTP诱导（100 Hz刺激一次），会诱导不依赖蛋白质合成的早期LTP（E-LTP），导致CPEB短暂磷酸化。然而，更强的刺激（100 Hz刺激四次），已知会诱导依赖蛋白质合成的L-LTP，会引发CPEB的长时间磷酸化。此外，CPEB磷酸化与PP1抑制剂多巴胺和cAMP调节的磷蛋白的磷酸化相关，后者是蛋白激酶A的已知底物。这些结果引出了一个假说，即CaMKII和蛋白磷酸酶对CPEB磷酸化的双向调节可能作为一种机制，通过刺激蛋白质合成从而稳定突触增强，将E-LTP转化为依赖蛋白质合成的L-LTP。
