2000
DOI: 10.1523/jneurosci.20-19-07246.2000
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Calcineurin-Mediated BAD Dephosphorylation Activates the Caspase-3 Apoptotic Cascade in Traumatic Spinal Cord Injury

Abstract: We report here that activation of the caspase-3 apoptotic cascade in spinal cord injury is regulated, in part, by calcineurin-mediated BAD dephosphorylation. BAD, a proapoptotic member of the bcl-2 gene family, is rapidly dephosphorylated after injury, dissociates from 14-3-3 in the cytosol, and translocates to the mitochondria of neurons where it binds to Bcl-x(L). Pretreatment of animals with FK506, a potent inhibitor of calcineurin activity, or MK801, an NMDA glutamate receptor antagonist, blocked BAD depho… Show more

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Cited by 177 publications
(139 citation statements)
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“…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).…”
Section: Discussionmentioning
confidence: 99%
“…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).…”
Section: Discussionmentioning
confidence: 99%
“…[24][25][26] Severe compression SCI increased caspase-3 activation as assayed by immunohistochemical staining (Figure 5a). Double immunolabeling with anti-NeuN and anticaspase-3 antibodies showed that active capase-3 is colocalized with some motor neuron cells in the lesioned spinal cord compared to that of surgical control (Figure 5a).…”
Section: Mouse Spinal Cord Compression Injury Modelmentioning
confidence: 99%
“…Interestingly, calcineurin is a calcium-dependent enzyme and its activation may also be involved in activation of nuclear factor-B and in apoptotic programs. 16,17 Thus, in dystrophic muscle CsA may counteract calcineurin activity, and consequently the pathological cascade related to the enzyme, at a step following its overactivation by the increase in calcium level.…”
Section: Csa Exerts Different Effects On Functional Cellular Parametementioning
confidence: 99%
“…15 In dystrophic muscle the calciumdependent activation of calcineurin may directly contribute to the chronic inflammatory state, through activation of nuclear factor-B, and to apoptotic pathways, via activation of the proapoptotic Bcl-2 member BAD. 16,17 Furthermore, CsA can exert calcineurin-independent effects on mitochondrial permeability pore, a mechanism effective in contrasting apoptosis in collagen VI-deficient muscular dystrophy and potentially important in view of the metabolic sufferance of DMD muscles. 5,18 However, the pharmacological inhibition of calcineurin may have controversial outcome because of the physiological roles of the enzyme in skeletal muscle.…”
mentioning
confidence: 99%