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

• Published in: The Journal of neuroscience 2005-02, Vol.25 (5), p.1281-1290
• Main Authors: Schmitt, John M, Guire, Eric S, Saneyoshi, Takeo, Soderling, Thomas R
• Format: Article
• Language: English
• Subjects: 2-Amino-5-phosphonovalerate - pharmacology; Animals; Benzimidazoles - pharmacology; Butadienes - pharmacology; Calcium-Calmodulin-Dependent Protein Kinase Kinase; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Calcium-Calmodulin-Dependent Protein Kinases - physiology; Cells, Cultured - drug effects; Cellular/Molecular; Colforsin - pharmacology; Excitatory Amino Acid Antagonists - pharmacology; Hippocampus - cytology; Hippocampus - enzymology; Hippocampus - physiology; Isoquinolines - pharmacology; Long-Term Potentiation - physiology; Male; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinase 1 - genetics; Mitogen-Activated Protein Kinase 1 - physiology; Mutation, Missense; N-Methylaspartate - pharmacology; Naphthalimides; Neurons - physiology; Nitriles - pharmacology; Protein Kinase Inhibitors - pharmacology; Protein Processing, Post-Translational; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Protein-Serine-Threonine Kinases - physiology; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; ras-GRF1 - metabolism; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate - drug effects; Receptors, N-Methyl-D-Aspartate - physiology; Recombinant Fusion Proteins - physiology
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.4086-04.2005

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.