Calcium apoptosis activation

Elevated cytoplasmic calcium activates a variety of enz3unes, with membrane-damaging effects. The major enz)unes that are involved in activation by calcium include ATPases, phospholipases, proteases, and endonucleases. Thus, increased calcium causes increased mitochondrial permeability and induction of apoptosis and necrosis. Calcium is required for maintenance and fxmction of the cytoskeleton as well (Dahm and Jones, 1996 Delgado-Coello et al., 2006). 

Increased intracellular calcium ions ([Ca j) have been demonstrated to act as an important mediator of apoptosis in a variety of cells (4S). Baek et al. (28) reported that ursolic acid induced apoptosis in HL-60 cells and increased intracellular calcium ions ([Ca jO. Although the precise mechanism by which [Ca Ji mediates apoptosis is not known, the Ca /Mg Mependent endonuclease, which cleaves double-strand DNA at nucleosome linker regions, remains an attractive target of Ca (IS). Some calcium-dependent/independent mechanisms nuy be involved in the apoptosis-inducing activity of camosic acid, camosol, and ursolic acid and remain a subject for further study. 

The CaR regulates numerous biological processes, including the expression of various genes (e.g., PTH) the secretion of hormones (PTH and calcitonin), cytokines (MCP-1), and calcium (e.g., into breast milk) the activities of channels (potassium channels) and transporters (aquaporin-2) cellular shape, motility (of macrophages), and migration cellular adhesion (of hematopoietic stem cells) and cellular proliferation (of colonocytes), differentiation (of keratinocytes), and apoptosis (of H-500 ley dig cancer cells) [3]. 

Mitochondrial permeability transition involves the opening of a larger channel in the inner mitochondrial membrane leading to free radical generation, release of calcium into the cytosol and caspase activation. These alterations in mitochondrial permeability lead eventually to disruption of the respiratory chain and dqDletion of ATP. This in turn leads to release of soluble intramito-chondrial membrane proteins such as cytochrome C and apoptosis-inducing factor, which results in apoptosis. 

Acute over-activation of NHE1 results in a marked elevation in intracellular sodium concentration with a subsequent increase in intracellular calcium, via the Na +/Ca++ exchanger. This in turn triggers a cascade of injurious events that can culminate in tissue dysfunction and ultimately apoptosis and necrosis. This is commonly seen in organs such as the heart, brain and kidneys as a consequence of ischemia-reperfusion. 

Deiva K, Geeraerts T, Salim H, Leclerc P, Hery C, Hugel B, Freyssinet JM, Tardieu M (2004) Fractalkine reduces N-methyl-d-aspartate-induced calcium flux and apoptosis in human neurons through extracellular signal-regulated kinase activation. Eur J Neurosci 20(12) ... 

Kruman 11, Nath A, Mattson MP (1998) HlV-1 protein Tat induces apoptosis of hippocampal neurons by a mechanism involving caspase activation, calcium overload, and oxidative stress. Exp Neurol 154(2) 276-288... 

Systematic cell degradation and death, apoptosis, on the other hand, is thought to be necessary to avoid cell damage accumulating so as to cause incorrect differentiation. The process is very complicated involving activation of a number of destructive enzymes where once more increase in cell calcium often initiates the hydrolyses using special internal calcium-dependent enzymes, calpains (see Demaurex in Further Reading). 

Fas ligand and interleukin-ip), the neurotransmitter glutamate and thrombin. Like tumor necrosis factor (TNF) receptors, Fas is coupled to downstream death effector proteins that ultimately induce caspase activation (Ch. 22). Fas and TNF receptors recruit proteins called FADD and TRADD respectively FADD and TRADD then activate caspase-8, which, in turn, activates caspase-3 (Fig. 35-4). Calcium ion influx mediates neuronal apoptosis induced by glutamate receptor activation calcium induces mitochondrial membrane permeability transition pore opening, release of cytochrome c and caspase activation. Interestingly, in the absence of neurotrophic factors some neurotrophic factor receptors can activate apoptotic cascades, the low-affinity NGF receptor being one example of such a death receptor mechanism [23],... 

Once apoptosis is triggered, a stereotyped sequence of premitochondrial events occurs that executes the cell death process. In many cases proteins and/or lipid mediators that induce changes in mitochondrial membrane permeability and calcium regulation are produced or activated. For example, the pro-apoptotic Bcl-2 family members Bax, Bad and Bid may associate with the mitochondrial membrane and modify its permeability. Membrane-derived lipid mediators such as ceramide and 4-hydroxynonenal can also induce mitochondrial membrane alterations that are critical for the execution of apoptosis. 

Several different changes in mitochondria occur during apoptosis. These include a change in membrane potential (usually depolarization), increased production of reactive oxygen species, potassium channel activation, calcium ion uptake, increased membrane permeability and release of cytochrome c and apoptosis inducing factor (AIF) [25]. Increased permeability of the mitochondrial membranes is a pivotal event in apoptosis and appears to result from the formation of pores in the membrane the proteins that form such permeability transition pores (PTP) may include a voltage-dependent anion channel (VDAC), the adenine nucleotide translocator, cyclophilin D, the peripheral benzodiazepine receptor, hexokinase and... 

The toxic effect of 7-oxysterols, 25- and 27-hydroxycholesterols and their involvement in LDL cytotoxicity have been extensively studied on the different vascular cell types (Lizard et al, 1999 Aupeix et al, 1995 Clare et al, 1995 Ramasamy et al, 1992). 7a and 7p-hydroxycholesterols, 7-ketocholesterol, 25 and 27-hydroxycholesterol induce apoptosis (Brown and Jessup, 1999 Lizard et al, 1999, 1998 Zhang et al, 1997 Hughes et al, 1994). 7p-hydroperoxycholesterol is one of the most toxic Oxysterols present in oxidized LDL (Brown and Jessup, 1999 Colles et al, 1996). 25-hydroxycholesterol, though less active (Aupeix et al 1995), is able to trigger a cytochrome c release and subsequent caspase activation in CHO cells, but also calcium inaease in relation with apoptosis (Rusinol et al, 2000). 

Oxysterol-mediated cytoxicity occurs by neaosis or apoptosis (Lizard et al, 1999 Yin et al, 2000), and can be partially prevented by Bcl2 overexpression (which inhibits caspase-3 activation and subsequent apoptosis), and by glutathione or antioxidants (Lizard et al, 1998). The mechanism of cytotoxicity is unclear but could involve an oxidative stress (Lizard et al, 1998), a direct stimulation of apoptotic cascade (Harada et al, 1997 Christ et al, 1993), a calcium rise (Spyridopoulos et al, 2001), or metabolic dysfunctions such as inhibition of HMGCoA reductase or incorporation of oxysterols into membranes (Brown and Jessup, 1999). 

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