Calmodulin-dependent kinase kinase/calmodulin kinase I activity gates extracellular-regulated kinase-dependent long-term potentiation

被引:123
作者
Schmitt, JM [1 ]
Guire, ES [1 ]
Saneyoshi, T [1 ]
Soderling, TR [1 ]
机构
[1] Oregon Hlth & Sci Univ, Vollum Inst, Portland, OR 97239 USA
关键词
calcium; CaM kinase; ERK; LTP; synaptic plasticity; eIF4E;
D O I
10.1523/JNEUROSCI.4086-04.2005
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Intracellular Ca2+ and protein phosphorylation play pivotal roles in long-term potentiation (LTP), a cellular model of learning and memory. Ca2+ regulates multiple intracellular pathways, including the calmodulin-dependent kinases (CaMKs) and the ERKs ( extracellular signal-regulated kinases), both of which are required for LTP. However, the mechanism by which Ca2+ activates ERK during LTP remains unknown. Here, we describe a requirement for the CaMK-kinase ( CaMKK) pathway upstream of ERK in LTP induction. Both the pharmacological inhibitor of CaMKK, STO-609, and dominant-negative CaMKI (dnCaMKI), a downstream target of CaMKK, blocked neuronalNMDAreceptor-dependent ERK activation. In contrast, an inhibitor of CaMKII and nuclear-localized dnCaMKIV had no effect on ERK activation. NMDA receptor-dependent LTP induction robustly activated CaMKI, the Ca2+-stimulated Ras activator Ras-GRF1 (Ras-guanyl-nucleotide releasing factor), and ERK. STO-609 blocked the activation of all three enzymes during LTP without affecting basal synaptic transmission, activation of CaMKII, or cAMP-dependent activation of ERK. LTP induction itself was suppressed similar to50% by STO-609 in a manner identical to the ERK inhibitor U0126: either inhibitor occluded the effect of the other, suggesting they are part of the same signaling pathway in LTP induction. STO-609 also suppressed regulatory phosphorylation of two downstream ERK targets during LTP, the general translation factors eIF4E ( eukaryotic initiation factor 4) and its binding protein 4E-BP1 ( eukaryotic initiation factor 4E-binding protein 1). These data indicate an essential role for CaMKK and CaMKI to link NMDA receptor-mediated Ca2+ elevation with ERK-dependent LTP.
引用
收藏
页码:1281 / 1290
页数:10
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