title: Calmodulin-dependent kinase kinase/calmodulin kinase I activity gates extracellular-regulated kinase-dependent long-term potentiation.
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 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.
authors.affiliation: Vollum Institute, Oregon Health and Sciences University, Portland, Oregon 97239, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Schmitt
authors.forename: Eric S
authors.initials: ES
authors.lastname: Guire
authors.forename: Takeo
authors.initials: T
authors.lastname: Saneyoshi
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Soderling
mesh_terms: D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D002070:Butadienes / Q000494:pharmacology; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology*; D002478:Cells, Cultured / Q000187:drug effects; D005576:Colforsin / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000201:enzymology / Q000502:physiology*; D007546:Isoquinolines / Q000494:pharmacology; D017774:Long-Term Potentiation / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000502:physiology*; D020125:Mutation, Missense; D016202:N-Methylaspartate / Q000494:pharmacology; D053644:Naphthalimides; D009474:Neurons / Q000502:physiology; D009570:Nitriles / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D020666:ras-GRF1 / Q000378:metabolism
chemical_list: D001562:Benzimidazoles; D002070:Butadienes; D018691:Excitatory Amino Acid Antagonists; D007546:Isoquinolines; D053644:Naphthalimides; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D011993:Recombinant Fusion Proteins; C458525:STO 609; C113580:U 0126; D020666:ras-GRF1; D005576:Colforsin; D016202:N-Methylaspartate; D015763:2-Amino-5-phosphonovalerate; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C517699:Camkk1 protein, mouse; C517701:Camkk1 protein, rat; D019950:Mitogen-Activated Protein Kinase 1