THE CALCIUM-ION AND CELL-DEATH

There is now convincing evidence that the calcium ion can play a criti cal role in cell killing in the central nervous system and other tissu es. Recent research has established some of the biochemical mechanisms by which intracellular Ca2+ overload can trigger either necrotic or a poptotic cell death, and a number of studies have shown that preventio n of Ca2+ overload by pretreatment with either Ca2+ chelators, recepto r antagonists or channel blockers can rescue cells that would otherwis e die. Similarly, cells which express high levels of certain Ca2+-bind ing proteins (e.g. calbindin-D28K) seem to be more resistant to killin g. Thus, it appears that the development of improved strategies to pre vent Ca2+ overload will be of importance for neuroprotection. The role of the calcium ion as intracellular regulator of many physiological p rocesses is now well established. Thus, the effects of a variety of ho rmones and growth factors have been found to be mediated by transient increases in the level of cytosolic Ca2+, which frequently assume osci llatory patterns (see Carafoli, 1989 and Berridge, 1991 for reviews). Most often, the Ca2+ increase is initiated by the release of Ca2+ from intracellular stores followed by the stimulation of influx of extrace llular Ca2+. Most regulatory effects of Ca2+ are mediated by Ca2+-bind ing proteins (e.g. calmodulin) and achieved by alterations of the phos phorylation state of target proteins. Along with this knowledge has co me the understanding that Ca2+ can also play a determinant role in a v ariety of pathological and toxicological processes. It has long been r ecognized that Ca2+ accumulates in necrotic tissue, and more recent wo rk has revealed that a disruption of intracellular Ca2+ homeostasis is frequently associated with the early development of cell injury (Scha nne et al., 1979; Jewell et al., 1982; Fleckenstein et al., 1983). Thi s led to the formulation of the calcium hypothesis of cell injury, pro posing that perturbation of intracellular Ca2+ homeostasis may be a co mmon step in the development of cytotoxicity. Support for this hypothe sis has come from a large number of studies demonstrating that the cal cium ion plays a critical role in cytotoxicity and cell killing in man y tissues, notably the central nervous system and the immune system (s ee Nicotera et al., 1992 for review).