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Calcium/calmodulin‐dependent protein kinase type IV (CaMKIV) inhibits apoptosis induced by potassium deprivation in cerebellar granule neurons
Author(s) -
SEE VIOLAINE,
BOUTILLIER ANNE-LAURENCE,
BITO HARUHIKO,
LOEFFLER JEAN-PHILIPPE
Publication year - 2001
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.00-0106com
Subject(s) - creb , camk , microbiology and biotechnology , calmodulin , apoptosis , biology , cerebellum , protein kinase a , neuroprotection , activator (genetics) , caspase 3 , phosphorylation , chemistry , transcription factor , programmed cell death , biochemistry , endocrinology , neuroscience , autophosphorylation , receptor , gene , enzyme
The neuroprotective mechanisms of the Ca 2+ /calmodulin kinase (CaMK) signaling pathway were studied in primary cerebellar neurons in vitro. When switched from depolarizing culture conditions HK (extracellular K + 30 mM) to LK (K + 5 mM), these neurons rapidly undergo nuclear fragmentation, a typical feature of apoptosis. We present evidence that blockade of L‐type Ca 2+ channels (nifedipine sensitive) but not N/P/Q‐type Ca 2+ channels (omega‐conotoxin MVIIC sensitive) triggered apoptosis and CPP32/ caspase‐3‐like activity. The entry into apoptosis was associated with a progressive caspase‐3‐dependent cleavage of CaMKIV, but not of CaMKII. CaMKIV function in neuronal apoptosis was further investigated by overexpression of CaMKIV mutants by gene transfer. A dominant‐active CaMKIV mutant inhibited LK‐induced apoptosis whereas a dominant‐negative form induced apoptosis in HK, suggesting that CaMKIV exerts neuroprotective effects. The transcription factor CREB is a well‐described nuclear target of CaMKIV in neurons. When switched to LK, the level of phosphorylation of CREB, after an initial drop, further declined progressively with kinetics comparable to those of CaMKIV degradation. This decrease was abolished by caspase‐3 inhibitor. These data are compatible with a model where Ca 2+ influx via L‐type Ca 2+ channels prevents caspase‐dependent cleavage of CaMKIV and promotes neuronal survival by maintaining a constitutive level of CaMKIV/CREB‐dependent gene expression.—Sée, V., Boutillier, A.‐L., Bito, H., Loeffler, J.‐P. Calcium/calmodulin‐dependent protein kinase type IV (CaMKIV) inhibits apoptosis induced by potassium deprivation in cerebellar granule neurons. FASEB J. 15, 134–144 (2001)