期刊
JOURNAL OF NEUROSCIENCE
卷 25, 期 5, 页码 1281-1290出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.4086-04.2005
关键词
calcium; CaM kinase; ERK; LTP; synaptic plasticity; eIF4E
资金
- NIDDK NIH HHS [DK007680, T32 DK007680] Funding Source: Medline
- NIGMS NIH HHS [R01 GM041292, GM41292] Funding Source: Medline
- NINDS NIH HHS [R01 NS027037, R01 NS27037] Funding Source: Medline
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.
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