Ca2+is a basic signalling factor involved in various basic biochemical and physiologicalprocesses, including contraction, secretion, cell proliferation and differentiationand cell death.During intracellular Ca2+ overload,ER andmitochondria take up Ca2+, which further results in ER/mitochondrialstress. ER stress compromises the ability to produce properly folded proteins,and misfolded or unfolded proteins will accumulate. At this point, two pathwaysmay be activated.

Activation of the ‘unfolded protein response’ normallycounteracts the effects of the original stress by maintaining theprotein-folding capacity of the ER. Initially, protein synthesis is inhibitedto temporarily stop production of new proteins. Subsequently, chaperone genesthat promote protein folding and translocation of misfolded proteins from the ERfor proteasome-dependent degradation are induced. In the ‘ER overload response’pathway the ER sends a signal to activate the nuclear factor ?B (NF-?B).

Themechanism of NF-?B activation is not entirely clear, but it has been suggestedthat reactive oxygen intermediates act as second messengers since antioxidants haveshown to inhibit NF-?B activation. NF-?B translocates to the nucleus where itactivates transcription of immune response and pro-inflammatory genes, such asinterferons and cytokines. Both pathways prevent accumulation of non-functionaland potentially toxic protein products, but may also contribute to theirelimination when abnormalities become too extensive, leading to cell death(Herr and Debatin, 2001; Orrenius et al., 2003; Lindholm et al.

, 2006; Lai etal., 2007). Prolonged ER stress may additionally activate pro-caspase-12, whichacts on effector caspases to induce apoptosis (Nakagawa et al., 2000).A rolefor excitotoxicity has been proposed in the aetiology and progression of many neurodegenerativediseases.

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Excitotoxicity is the term referring to neuronal injury induced byexcessive or prolonged activation of glutamate receptors, with a subsequentrise in intracellular Ca2+. The ability of neurons to preventexcitotoxic damage is related to their Ca2+ buffering capacity,accomplished by Ca2+ binding proteins and Ca2+sequestration in mitochondria and the ER. It is generally accepted that duringintracellular Ca2+ overload, these organelles take up Ca2+,which may infer stress and dysfunction of the organelles (see ‘Ca2+homeostasis’).

The elevated cytoplasmic Ca2+ will further amplifythe process of glutamate exocytosis. Next to this Ca2+inducedvesicular release, release of intracellular cytosolic glutamate, due to celllysis and slowing or reversal of glutamate transporters subsequent to depolarization,will additionally contribute to elevated glutamate concentrations in thesynaptic cleft. This process that has been called the ‘glutamatergic loop’includes the spreading of excitotoxicity to neighbouring cells (Doble., 1999).Ca2+ is also closely linked to the onset of cell deathpathways, such ascytochrome c release which is shown to be Ca2+dependent, with orwithout opening of the PTP (Brustovetsky et al., 2002). An elevated mitochondrialCa2+ stimulates mitochondrial dehydrogenases, which are key sitesfor NADH synthesis and mitochondrial energy production (Denton, 1988). Anintracellular Ca2+increase can furthermore induce the translocationof Bax, an apoptosis inducing protein, to mitochondria (Smaili et al.

, 2009),resulting in pore formation and interaction with the permeability transitionpore (PTP) components by binding to the voltage-dependent anion channel (VDAC)(Shimizu et al., 1999). PTP opening can also be induced by high Ca2+in the mitochondrial matrix, oxidativestress, thiol oxidation and low ??m.

Mitochondrial swelling may additionally lead to permeabilization of themitochondrial membranes, allowing Ca2+ and other low-molecular-massmatrix components such as cytochrome c to leave the mitochondria. Release ofcytochrome c activates caspases that execute cell death(Orrenius et al., 2003).