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

John M. Schmitt, Eric S. Guire, Takeo Saneyoshi, Thomas Soderling

    Research output: Contribution to journalArticle

    114 Citations (Scopus)

    Abstract

    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 Ca 2+-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.

    Original languageEnglish (US)
    Pages (from-to)1281-1290
    Number of pages10
    JournalJournal of Neuroscience
    Volume25
    Issue number5
    DOIs
    StatePublished - Feb 2 2005

    Fingerprint

    Calcium-Calmodulin-Dependent Protein Kinases
    Long-Term Potentiation
    Extracellular Signal-Regulated MAP Kinases
    Phosphotransferases
    N-Methyl-D-Aspartate Receptors
    Calcium-Calmodulin-Dependent Protein Kinase Type 2
    ras-GRF1
    Carrier Proteins
    Phosphorylation
    Eukaryotic Initiation Factor-4E
    Synaptic Transmission
    Nucleotides
    Learning
    Pharmacology

    Keywords

    • Calcium
    • CaM kinase
    • eIF4E
    • ERK
    • LTP
    • Synaptic plasticity

    ASJC Scopus subject areas

    • Neuroscience(all)

    Cite this

    Calmodulin-dependent kinase kinase/calmodulin kinase I activity gates extracellular-regulated kinase-dependent long-term potentiation. / Schmitt, John M.; Guire, Eric S.; Saneyoshi, Takeo; Soderling, Thomas.

    In: Journal of Neuroscience, Vol. 25, No. 5, 02.02.2005, p. 1281-1290.

    Research output: Contribution to journalArticle

    Schmitt, John M. ; Guire, Eric S. ; Saneyoshi, Takeo ; Soderling, Thomas. / Calmodulin-dependent kinase kinase/calmodulin kinase I activity gates extracellular-regulated kinase-dependent long-term potentiation. In: Journal of Neuroscience. 2005 ; Vol. 25, No. 5. pp. 1281-1290.
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