Calcium and Cellular Death

Abstract

Calcium (Ca²⁺) ions are ubiquitous intracellular messengers governing innumerable functions such as the control of cell growth and differentiation, membrane excitability, exocytosis and synaptic activity. Because of this, neurons must tightly regulate the cytosolic Ca²⁺ concentration ([Ca²⁺]_i) to achieve a sufficiently high signal-to-noise ratio for efficient Ca- signaling to occur. The resting free [Ca²⁺]_i must remain at very low levels (around 100 nM, or 10⁵ times lower than extracellular [Ca²⁺]), so that relatively small or localized increases in [Ca²⁺]_i can be used to trigger physiological events such as the activation of an enzyme or an ion channel. Neurons have therefore evolved complex homeostatic mechanisms to control both [Ca²⁺]_i and the intracellular location of Ca²⁺ ions (for a general review of Ca²⁺ homeostasis in neurons see refs Blaustein, 1988; Meldolesi et al. 1988; Smith, Augustine, 1988; Miller, 1992). These mechanisms consist of complex interactions between four general categories of events: Ca²⁺ influx, Ca²⁺ buffering, internal Ca²⁺ storage and Ca²⁺ efflux. Under physiological conditions, a delicate interplay between these processes allows multiple Ca²⁺ dependent signaling cascades to be regulated independently within the same cell. However, it is widely believed that excessive Ca²⁺ loading, exceeding the capacity of Ca-regulatory mechanisms, may inappropriately activate Ca-dependent processes which either lie dormant or normally operate at low levels. When over-activated, such processes directly damage neurons or lead to the formation of toxic reaction products which ultimately cause cell death. However, in spite of two decades of research supporting the association between Ca²⁺ excess and neurotoxicity, the precise molecular mechanisms by which Ca²⁺ toxicity occurs remain poorly understood.