High Level Calcineurin Activity Predisposes Neuronal Cells to Apoptosis

Abstract

Calcineurin is a Ca2؉ /calmodulin-dependent protein phosphatase that is abundantly expressed in several specific areas of the brain, which are exceptionally vulnerable to stroke, epilepsy, and neurodegenerative diseases. In this study, we assessed the effects of high level activity of calcineurin on neuronal cells. Virus-mediated high level constitutive activity of calcineurin rendered neuronal cells susceptible to apoptosis induced by serum reduction or by a brief exposure to calcium ionophore. Adenovirus-mediated, high level forced activity of calcineurin induced cytochrome c/caspase-3-dependent apoptosis in neurons. Preincubation with the calcineurin inhibitors cyclosporin A and FK506 reduced susceptibility to apoptosis. High level constitutive expression of Bcl-2 or CrmA or incubation with a specific caspase-3 inhibitor inhibited the calcineurin-induced apoptosis. These data indicate that high level constitutive activity of calcineurin predisposes neuronal cells to cytochrome c/caspase-3 dependent apoptosis even under sublethal conditions.

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).…”

“…One of the consequences of calcium entering into the cell is the activation of several enzymes, namely, calcineurin. 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).…”

Myelin associated glycoprotein cross-linking triggers its partitioning into lipid rafts, specific signaling events and cytoskeletal rearrangements in oligodendrocytes

“…Fragments of fodrin (120-150 kDa) are generated by caspase and calpain activation during apoptotic cell death (Moore et al, 2002). Ca 2+ /calmodulin-dependent protein phosphatases, such as calcineurin (Asai et al, 1999), also regulate the phosphorylation of LDH, which is dephosphorylated upon MAG cross-linking. Changes in the phosphorylation of LDH have important implications for the control of cell metabolism (Yasykova et al, 2000).…”

Spatial and Intracellular Distribution of the Endogenous Calcineurin-Inhibitory Proteins, ZAKI-4, in Mouse Brain

“…It also plays a role in brain ischemia [3,29] and neural cell apoptosis [1]. Furthermore, recent reports have suggested that calcineurin is involved in the pathogenesis of schizophrenia because conditional calcineurin knockout mice exhibit multiple abnormal behaviors related to schizophrenia [17].…”