Calcineurin and mitochondrial function in glutamate‐induced neuronal cell death

Abstract

We have previously reported that glutamate can trigger a succession of necrosis and apoptosis in cerebellar granule cells (CGC). Since specific blockers of the N-methyl-aaspartate (NMDA) receptor channel prevented both types of cell death, the role of Ca2+-dependent processes in the initiation of glutamate toxicity was further investigated. We examined the possible involvement of mitochondria and the role of the Ca2÷/ calmodulin-regulated protein phosphatase, calcineurin, in the development of either type of cell death. Cyclosporin A and the more selective calcineurin inhibitor, FK-506, prevented the development of both early necrosis and delayed apoptosis. In addition, cyclosporin A prevented the collapse of mitochondrial membrane potential observed during the exposure to glutamate and the concomitant necrotic phase. When CsA was added immediately after glutamate removal, it also prevented delayed apoptosis of neurons that bad survived the necrotic phase. Altogether, these results suggest the involvement of calcineurin and a role for mitochondrial decnergization as early signals in neuronal apoptosis induced by glutamate.

FK506 prevents mitochondrial-dependent apoptotic cell death induced by 3-nitropropionic acid in rat primary cortical cultures

“…Dephosphorylated Bad translocates from the cytosol to the mitochondria where it inhibits antiapoptotic activity of Bcl-2 and Bcl-x L , ultimately, leading to cell death (Desagher and Martinou, 2000, for review). In accordance, was found to decrease apoptosis of cerebellar granule and cortical cultures after exposure to glutamate (Ankarcrona et al, 1996;Asai et al, 1999) or to amyloidogenic peptides (Agostinho and Oliveira, 2003). FK506 also prevented calcineurin-mediated dephosphorylation of nitric oxide synthase, leading to neuroprotection (Dawson et al, 1993;Nishino et al, 1996).…”

“…This calcium-dependent phosphatase has been described to be involved in many pathways that ultimately lead to cell death (Asai et al, 1999;Springer et al, 2000). Accordingly, inhibition of calcineurin as a relevant event in FK506-mediated protective effects has been demonstrated by many authors (Ankarcrona et al, 1996;Asai et al, 1999;Mobley and Agrawal, 2003;Nishino et al, 1996;Stevens et al, 2003). However, numerous other studies have excluded a substantial contribution of inhibited calcineurin for neuroprotection exerted by FK506 (Sabatini et al, 1997;Snyder et al, 1998;Toung et al, 1999;Yardin et al, 1998).…”

“…Calcineurin regulates a number of transcription factors and ion channels and is involved in long-term depression of postsynaptic potential and synaptic vesicle recycling (Crabtree, 2001;Kramer et al, 2003). Calcineurin has been also implicated in neuronal cell death induced by insults that elevate cytosolic calcium (Ankarcrona et al, 1996;Agostinho and Oliveira, 2003;Wang et al, 1999;Wood and Bristow, 1998). Calcineurin can promote apoptosis through dephosphorylation of Bad at 112 Ser and 136 Ser (Wang et al, 1999), a proapoptotic member of the Bcl-2 family.…”

Dissociation of mitochondrial depolarization from cytochrome c release during apoptosis induced by photodynamic therapy

“…An example of cells treated with 300 nM Pc 4 and 90 mJ/cm 2 of red light is displayed in Figure 4. In control untreated cells, JC-1 fluorescence was found to have a perinuclear distribution and a punctuate pattern, indicating its location in mitochondria (Ankarcrona et al, 1996). A slight reduction in JC-1 fluorescence was observed in cells 15 min after receiving 90 mJ/cm 2 .…”

Wallerian-like axonal degeneration in the optic nerve after excitotoxic retinal insult: an ultrastructural study

“…Evidence is also available that the excitotoxic injury can produce hybrid forms of cell death, existing on a continuum between the classically defined apoptosis and necrosis [38,39,43], and is likely to depend on the degree of insult and the sensitivity of the exposed neurones. Time-dependent studies of glutamate exposure to cultured neuronal populations showed that the excitotoxins induce early necrosis and delayed apoptosis [36,44]. There is also evidence that the necrotic neurons may completely recover to undergo apoptotic transformation later [44].…”