Apoptosis calmodulin

Keywords calmodulin dependent protein kinase, kinase cascade, cell cycle regulation, apoptosis,... 

See, V., Boutillier, A. L., Bito, H. and Loeffler, J. P., 2001, Calcium/calmodulin-dependent protein kinase type TV (CaMKIV) inhibits apoptosis induced by potassium deprivation in cerebellar granule neurons, Faseb J, 15, pp 134-144. 

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). 

Calmodulin, poly(ADP-ribose)polymerase and p53 are targets for modulating the effects of sulfur mustard (Rosenthal et al, 2000). It was tested whether calmodulin mediates the mitoehondrial apoptotic pathway induced by SM in human keratinoeytes. Of the three human CaM genes, the predominant form expressed was CaMl. These results indicate that CaM, ealeineurin, and Bad also play a role in SM-induced apoptosis, and may therefore be targets for therapeutic intervention to reduce SM injury (Simbulan-Rosenthal et al, 2006). 

Studies have revealed consequences of P-AR stimulation beyond regulating the rate and strength of myocyte contraction. Chronic stimulation of the PrAR induces myocyte apoptosis, although the signaling pathway is controversial (12,63,64). In vitro studies suggest that this process requires PKA-independent activation of intracellular Ca2+ through L-type Ca2+ channels, which leads to Ca2+ release from sarcoplasmic reticulum and subsequent activation of calmodulin kinase II in adult cardiac myocytes (65). However, this prAR-stimulated proapoptotic effect appears to be blocked by PKA inhibition in adult rat myocytes (63). In contrast, activation of P2-ARs has an antiapoptotic effect, which is mediated by the Py-subunits of G, in both rat and mouse adult cardiac myocytes... 

Dowd, D.R., P.N. MacDonald, B.S. Komm, M.R. Haussler and R. Miesfeld. Evidence for early induction of calmodulin gene expression in lymphocytes undergoing glucocorticoid-mediated apoptosis. J. Biol. Chem. 266 18423-18426, 1991. 

Rosenthal, D.S., Simbulan Rosenthal, C.M., Iyer, S., Spoonde, A., Smith, W., Ray, R., and Smulson, M.E. (1998). Sulfur mustards induces markers of terminal differentiation and apoptosis in keratinoc)4es via a Ca -calmodulin and caspase-dependent pathway. J Invest Dermatol 111, 64-71. 

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. 

---