Apoptosis calcineurin

Sustained cytosolic Ca2+ overload usually results in a different route leading to cell death. It mainly relies on the activation of the calcium/calmodulin (CaM)-dependent phosphatase, calcineurin. Calcineurin-catalyzed dephosphorylation promotes apoptosis by regulating the activity of a number of downstream targets, including the pro-apoptotic Bcl-2 family member, Bad (Wang, et al., 1999), and transcription factors of the NFAT (nuclear factor of activated T cells) family (Rao, et al., 1997). There are also other Ca2+-dependent enzymes contributing to the apoptotic events, and they include several DNA-degrading endonucleases (Robertson, et al., 2000) and Ca2+-activated cystein proteases of the calpain family essential for the enzymatic activation of the crucial pro-apoptotic effectors (Altznauer, et al., 2004). 

Calcineurin. The calcineurin, or Ca2+-calmodulin dependent protein phosphatase (Aramburu et al., 2004) mediates apoptosis through at least two routes. First, this action can be achieved through steroid receptor Nur77 and CD95 ligand this pathway was found in lymphoid cells (Shi et al., 1989). Alternatively, calcineurin dephosphorylates a pro-apoptotic protein Bad (a member of Bcl-2 family), which in turn translocates into mitochondria and triggers release of cytochrome C and activation of caspases (Wang et al., 1999). 

I. 2000. p-adrenergic pathway induces apoptosis through calcineurin activation in cardiac myocytes. J. Biol. Chem. 275 34528-34533. 

T. Kakita, K. Hasegawa, E. Iwai-Kanai, S. Adachi, T. Morimoto, H. Wada, T. Kawamura, T. Yanazume and S. Sasayama, Calcineurin pathway is required for endothelin-1-mediated protection against oxidant stress-induced apoptosis in cardiac myocytes, Circ. Res. 88(12), 1239-1246 (2001). 

Higher eukaryotes PMOR General redox state Plasma membrane Ca + flux signal apoptosis through calcineurin( ) [104]... 

The hallmark feature of the Bcl-2 proteins is their ability to form hetero-or homodimers [69-71], The BH domains are the key to this property and form a-helical structures that serve as protein protein interaction motifs. For example, the BH4 domain (found in most, but not all anti-apoptotic family members) may be responsible for molecular interactions with calcineurin and Raf-1 [72, 73], The importance of the BH4 domain is emphasised by the fact that in cells transfected with a mutant or truncated form of Bcl-2 (an anti-apoptotic protein) apoptosis is accelerated [74,75], There is also some evidence that this BH4 domain may be involved in control of the voltage-dependent anion channel of mitochondria [76], Some pro-apoptotic proteins (e.g. Bik, Bid and Bad) only possess the BH3 domain. Consequently, this has led to the idea that this domain is the minimal death domain required for the activity of some pro-apoptotic proteins. 

Wolvetang, E.J., J.A. Larm, P. Moutsoulas, and A. Lawen. 1996. Apoptosis induced by inhibitors of the plasma membrane NADH-oxidase involves Bcl-2 and calcineurin. Cell Growth Differ. 7(10) 1315-1325. 

Changes in intracellular calcium levels are known to activate the mitochondrial pathway of apoptosis. A key regulator of Ca -dependent proteins is calmodulin. SM has been shown to cause a time-dependent induction of calmodulin in keratinocytes (Simbulan-Rosenthal et al., 2006). Moreover, depletion of calmodulin using antisense probes attenuated SM-induced activation of caspases involved in the mitochondrial pathway of apoptosis. Both antisense and pharmacological inhibition of calmodulin prevented SM-induced nuclear fragmentation in the keratinocytes. Bad, a proapoptotic Bcl-2 family member present in an inactive phosphorylated form in viable cells, was also activated by SM. Furthermore, cyclosporine A, a selective inhibitor of calcineurin, a Bad phosphatase, inhibited SM-induced keratinocyte apoptosis. These results suggest that calcium-dependent activation of Bad may be a mechanism by which SM induces apoptosis in keratinocytes. 

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