Activity-dependent synaptogenesis: regulation by a CaM-kinase kinase/CaM-kinase I/betaPIX signaling complex.
Neuron
; 57(1): 94-107, 2008 Jan 10.
Article
em En
| MEDLINE
| ID: mdl-18184567
ABSTRACT
Neuronal activity augments maturation of mushroom-shaped spines to form excitatory synapses, thereby strengthening synaptic transmission. We have delineated a Ca(2+)-signaling pathway downstream of the NMDA receptor that stimulates calmodulin-dependent kinase kinase (CaMKK) and CaMKI to promote formation of spines and synapses in hippocampal neurons. CaMKK and CaMKI form a multiprotein signaling complex with the guanine nucleotide exchange factor (GEF) betaPIX and GIT1 that is localized in spines. CaMKI-mediated phosphorylation of Ser516 in betaPIX enhances its GEF activity, resulting in activation of Rac1, an established enhancer of spinogenesis. Suppression of CaMKK or CaMKI by pharmacological inhibitors, dominant-negative (dn) constructs and siRNAs, as well as expression of the betaPIX Ser516Ala mutant, decreases spine formation and mEPSC frequency. Constitutively-active Pak1, a downstream effector of Rac1, rescues spine inhibition by dnCaMKI or betaPIX S516A. This activity-dependent signaling pathway can promote synapse formation during neuronal development and in structural plasticity.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Sinapses
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Transdução de Sinais
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Proteínas de Ciclo Celular
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Fatores de Troca do Nucleotídeo Guanina
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Espinhas Dendríticas
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Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina
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Proteína Quinase Tipo 1 Dependente de Cálcio-Calmodulina
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Neurônios
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2008
Tipo de documento:
Article