Calcium and Cell Death

Abstract

The key role of Ca²⁺ ions (Ca²⁺) for the function of excitable tissues was already described in 1882 in the classical experiments by Ringer. Since then, a plethora of cellular functions have been found to require Ca²⁺ signals or simply the maintenance of a set Ca²⁺ concentration. The major requirement for the signaling function of Ca²⁺ is the existence of a concentration gradient between the interstitial fluid and the interior of the cell. Whereas extracellular concentrations of free Ca²⁺ range between 1.3 and 1.8 mM, the free intracellular Ca²⁺ concentration ([Ca²⁺]i) is about 100 nM. Thus, cells are continuously faced with the problem of maintaining a concentration gradient of more than four orders of magnitude across the plasma membrane. Various physiological stimuli increase [Ca²⁺]i transiently and thereby induce cellular responses. However, under pathological conditions, changes of [Ca²⁺]i are generally more pronounced and sustained. Pronounced elevations of [Ca²⁺]i activate hydrolytic enzymes, lead to exaggerated energy expenditure, impair energy production, initiate cytoskeletal degradation, and ultimately result in cell death. Such Ca²⁺-induced cytotoxicity may play a major role in several neuropathological phenomena including chronic neurodegenerative diseases as well as acute neuronal losses (i.e., during the pathogenesis of stroke).