Calcium/calmodulin‐dependent protein kinase type IV (CaMKIV) inhibits apoptosis induced by potassium deprivation in cerebellar granule neurons

Abstract

The neuroprotective mechanisms of the Ca2+/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 Ca2+ channels (nifedipine sensitive) but not N/P/Q-type Ca2+ 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 Ca2+ influx via L-type Ca2+ channels prevents caspase-dependent cleavage of CaMKIV and promotes neuronal survival by maintaining a constitutive level of CaMKIV/CREB-dependent gene expression.

Tau accumulation induces synaptic impairment and memory deficit by calcineurin-mediated inactivation of nuclear CaMKIV/CREB signaling

“…As a key regulator of neuronal gene expression, phosphorylation of CaMKIV by Ca 2+ /CaM increases the activity and promotes the nuclear translocation of CaMKIV (57). Upon phosphorylation, the catalytically active CaMKIV gains access to the nuclei where it activates CREB-dependent gene expression (58,59). The nuclear translocation of CaMKIV is also regulated by importin-α (60).…”

Calcium/calmodulin-dependent kinase IV controls glucose-induced Irs2 expression in mouse beta cells via activation of cAMP response element-binding protein

“…CaMK IV is a multifunctional enzyme whose function is best understood in neurons, where it inhibits apoptosis and stimulates growth in a calcium-and CREB-dependent manner [23,[33][34][35][36][37]. CamkIV is also expressed by pancreatic beta cells [24], but its roles in beta cells have not been fully defined.…”

Repression of Ca2+/Calmodulin-dependent Protein Kinase IV Signaling Accelerates Retinoic Acid-induced Differentiation of Human Neuroblastoma Cells

“…We also investigated the potential for CaMKIV to function in a prosurvival capacity in BE(2)C cells as in other cell types, as has been reported (31,37,52,53). Silencing of CaMKIV expression in BE(2)C cells by RNAi increased the level of processed (cleaved) PARP and reduced the level of intact pro-caspase 3, events associated with the induction of apoptosis (Fig.…”

“…Apoptosis of cerebellar or spiral ganglia neurons due to withdrawal of trophic support may be counteracted by depolarization-induced Ca 2ϩ influx. However, in the absence of either trophic support or depolarizing medium, neuronal viability can still be maintained by transfection of CA-CaMKIV (52,53,66,67). In transgenic mice expressing catalytically inactive CaMKIV, there is a reduction in the number of thymic T lymphocytes and in T cell survival (31).…”