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Trophic agents that prevent neuronal apoptosis activate calpain and down‐regulate CaMKIV
Author(s) -
TremperWells Barbara,
Mathur Anjili,
BeamanHall Carol M.,
Vallano Mary Lou
Publication year - 2002
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2002.00829.x
Subject(s) - calpain , creb , microbiology and biotechnology , biology , phosphorylation , signal transduction , proteolysis , protein kinase a , nmda receptor , kinase , protein kinase c , transcription factor , receptor , biochemistry , enzyme , gene
CaMKIV is enriched in neuronal nuclei and mediates Ca 2+ ‐dependent survival via transcription factor phosphorylation. Cultured cerebellar granule neurons were used to examine whether distinct modes of Ca 2+ signaling differentially modulate CaMKIV expression and function. For long‐term survival, these neurons require 25 m m KCl or NMDA, which stimulates Ca 2+ entry through voltage‐sensitive Ca 2+ channels or NMDA receptors (NRs). Lower levels of Ca 2+ entry through NRs support survival of a neuronal subpopulation grown in 5 m m KCl media. Several effects were demonstrated: (i) sustained exposure to 25 m m KCl or 140 µ m NMDA produced CaMKIV down‐regulation, compared to 5 m m KCl cultures; (ii) CaMKIV down‐regulation was attenuated by nifedipine, APV and CaM kinase inhibitors, indicating that it is Ca 2+ 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 Ca 2+ and CaMKIV signaling pathway by these agents.