Trophic agents that prevent neuronal apoptosis activate calpain and down-regulate CaMKIV.
J Neurochem
; 81(2): 314-24, 2002 Apr.
Article
en En
| MEDLINE
| ID: mdl-12064479
CaMKIV is enriched in neuronal nuclei and mediates Ca2+-dependent survival via transcription factor phosphorylation. Cultured cerebellar granule neurons were used to examine whether distinct modes of Ca2+ signaling differentially modulate CaMKIV expression and function. For long-term survival, these neurons require 25 mm KCl or NMDA, which stimulates Ca2+ entry through voltage-sensitive Ca2+ channels or NMDA receptors (NRs). Lower levels of Ca2+ entry through NRs support survival of a neuronal subpopulation grown in 5 mm KCl media. Several effects were demonstrated: (i) sustained exposure to 25 mM KCl or 140 microM NMDA produced CaMKIV down-regulation, compared to 5 mM KCl cultures; (ii) CaMKIV down-regulation was attenuated by nifedipine, APV and CaM kinase inhibitors, indicating that it is Ca2+ dependent and reversible; (iii) down-regulation was both selective for nuclear substrates and calpain-mediated; (iv) proteolysis was exacerbated by leptomycin B, a nuclear export inhibitor. Although CaMKIV proteolysis by trophic agents seems paradoxical in light of evidence supporting its critical role in survival, the CaMKIV/CREB signal transduction pathway was preserved, as assessed by CaM kinase-mediated CREB phosphorylation, and the ability of CaM kinase inhibitors to interfere with KCl-mediated survival. We hypothesize that limited calpain-mediated proteolysis of CaMKIV is a negative feedback response to the sustained activation of a Ca2+ and CaMKIV signaling pathway by these agents.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Cloruro de Potasio
/
Calpaína
/
N-Metilaspartato
/
Receptores Citoplasmáticos y Nucleares
/
Proteínas Quinasas Dependientes de Calcio-Calmodulina
/
Neuronas
Límite:
Animals
Idioma:
En
Revista:
J Neurochem
Año:
2002
Tipo del documento:
Article
País de afiliación:
Estados Unidos
Pais de publicación:
Reino Unido