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The Journal of Neuroscience, February 2, 2005, 25(5):1281-1290; doi:10.1523/JNEUROSCI.4086-04.2005

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Cellular/Molecular
Calmodulin-Dependent Kinase Kinase/Calmodulin Kinase I Activity Gates Extracellular-Regulated Kinase-Dependent Long-Term Potentiation

John M. Schmitt, ^* Eric S. Guire, ^* Takeo Saneyoshi, and Thomas R. Soderling

Vollum Institute, Oregon Health and Sciences University, Portland, Oregon 97239

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 neuronal NMDA receptor-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 50% 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.

Key words: calcium; CaM kinase; ERK; LTP; synaptic plasticity; eIF4E

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Received Oct 1, 2004; revised December 16, 2004; accepted December 20, 2004.

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