Calcium level-induced apoptosis

Figure 9. Schematic of Gs-couplcd receptors. This type of receptor is coupled to adcnyl cyclase (AC) via the activated stimulatory Gs protein and leads to the formation of c-AMP. c-AMP in turn activates protein kinase A (PKA). PKA regulates calcium homeostasis and may induce apoptosis due to the elevation of intracellular calcium levels or prevent apoptosis by inactivating the proapoptotic Bad. p, and p2 adrenergic signaling pathways are mediated through this receptor. For PKA targeted proteins, see figure 17.

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. 

ABSTRACT In mammals, nitric oxide (NO) is a reactive free radical involved in diverse physiological functions. NO and its redox-related forms NO+ and NO react with di(oxygen) and its derivatives, with metalloproteins and thiol-containing proteins. NO-mediated nitrosation of proteins represents an important cellular regulatory mechanism. Biosynthesis of NO is catalysed by nitric oxide synthase (NOS). Three isoenzymes representing distinct gene products have been identified the inducible NOS isoform, the constitutive neuronal and endothelial isoforms. Inducible and constitutive NOSs have the same structural features, but their activities differ in their dependence to calcium and the rate of NO produced. The principal NO-mediated functions in mammals are endothelium-dependent relaxation, neurotransmission and immune response. The role of NO in the antitumor immune response comprises both regulatory and effector functions at the intra- or inter-cellular level. The first function includes inhibition of lymphocyte proliferation or participation in different transduction pathways. The second fiinction includes pro- or anti-tumoral effects and NO-mediated cell toxicity or cell resistance to apoptosis. 

Apoptosis is also induced by intracellular signals indicating that cell death should occur. Examples of these signals include growth factor withdrawal, cell injury, the release of certain steroids, and an inability to maintain low levels of intracellular calcium. All of these treatments, or changes, lead to release of cytochrome c from the mitochondria (Fig. 18.15). Cytochrome c is a necessary protein component of the mitochondrial electron transport chain that is a loosely bound to the outside of the inner mitochondrial membrane. Its release initiates apoptosis. 

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