FIGURE. The role of calcium in cellular injury.

Under normal conditions, there is a 10,000-fold Ca²⁺-gradient between the intra- and extracellular space. When cellular oxygen levels reach below-threshold levels, the Na⁺-K⁺-pump, which consumes 70% of neuronal ATP, fails, leading to depolarization of the membrane and influx of Ca²⁺ through VGCC and glutamate release into the synaptic cleft. Glutamate binds to NMDA, AMPA and KA receptors, leading to direct and indirect influx of Ca²⁺ into the cell. Elevated levels of intracellular Ca²⁺ lead to further calcium-induced calcium release (CICR) via binding of Ca²⁺ to CaM. CICR is mediated by RyR binding and calcium release from the sarcoendoplasmatic reticulum, the largest store of intracellular Ca²⁺. Increases in intracellular Ca²⁺ cannot be compensated for by the energy-dependent SERCA pump, located in the membrane of the sarcoendoplasmatic reticulum. A reduction in endoplasmic Ca²⁺ results in misfolding of proteins, leading to UFR as a cellular stress response. Influx of Ca²⁺ into mitochondria leads to formation of oxygen radicals and energy failure through decreased production of ATP. Binding of Ca²⁺ to CaM also leads to activation of NOS and formation of NO. Oxygen radicals react with NO to form peroxinitrite, a highly reactive molecule that damages DNA and proteins. DNA cleavage activates the DNA-repair enzyme PARP, which requires ATP for its action. PARP-related energy depletion adds further to cellular stress causing necrosis. The increased (toxic) levels of intracellular Ca²⁺ lead to increased mitochondrial permeability via MtPTP. This causes mitochondria to become permeable to molecules smaller than 1.5 kDa, which increases the osmolar load inside the mitochondria, causing mitochondrial swelling and outer membrane rupture, releasing CyC. CyC activates pro-apoptotic factors (caspases) by reacting with Ca²⁺-activated calpain. Elevated intracellular Ca²⁺ activates phospholipase A2 which cleaves cell membrane phospholipids, releasing arachidonic acid, which in turn can be further activated to proinflammatory molecules, such as prostaglandins, leukotrienes, and thromboxanes (not shown). Dantrolene is neuroprotective by blocking ryanodine receptors at the sarcoendoplasmatic reticulum, and thereby inhibiting further increase in intracellular Ca²⁺-levels.