Increase, intracellular calcium leads to Apoptosis

The duration and extent of Ca²⁺ influx may determine whether cells survive, die by apoptosis, or undergo necrotic lysis (Choi 1995). According to this paradigm, continuous, but  moderate increases in [Ca²⁺]_i such as those produced by a sustained slow influx may cause apoptosis, whereas an exceedingly high influx rate would cause rapid cell lysis (Nicotera et al., 1998). For instance, collaborative work with Dr Stuart A. Lipton’s laboratory has shown that stimulation of cortical neurons with high concentrations of NMDA results in necrosis, whereas exposure to lower concentrations causes apoptosis (Bonfoco et al., 1995). Correspondingly, neuronal death in experimental stroke models is necrotic in the ischemic core, but delayed and apoptotic in the less severely compromised penumbra or border regions (Li et al., 1995; Charriaut-Marlangue et al., 1995). Further studies in our laboratories have shown that intracellular energy levels are rapidly dissipated in necrosis, but not in apoptosis (Cox et al., 1990; Matson et al., 1989). These results suggest that while initial events may be common to both types of cell death, certain metabolic conditions would be required to activate downstream controllers, which direct cells towards the organized execution of apoptosis (Leist and Nicotera 1997).