CALCIUM SIGNALING AND THE REGULATION OF APOPTOSIS

Apoptotic cell death is characterized by cell shrinkage, chromatin con densation and fragmentation, formation of apoptotic bodies and phagocy tosis (Kerr el nl., 1972). At the molecular level, activation of a fam ily of cysteine proteases, caspases, related to interleukin-1 beta-con verting enzyme is believed to be a crucial event in apoptosis. This is associated with the proteolysis of nuclear and cytoskeletal proteins, cell shrinkage, glutathione efflux, exposure of phosphalidylserine on the cell surface, membrane blebbing, etc. In CD95- or TNF-mediated ap optosis, the proteolytic cascade is believed to be triggered directly by caspase binding to the activated plasma membrane receptor complex. In other forms of apoptosis, the mechanisms of activation of the prote olytic cascade are less well established but may involve imported prot eases, such as granzyme B, or factors released from the mitochondria a nd, possibly, other organelles. Recently, the possibility that cytochr ome c released from the mitochondria may serve to activate dormant cas pases in the cytosol, and thereby to propagate the apoptotic process, has attracted considerable attention. A perturbation of intracellular Ca2+ homeostasis has been found to trigger apoptosis in many experimen tal systems, and the apoptotic process has been related to either a su stained increase in cytosolic free Ca2+ level or a depletion of intrac ellular Ca2+ stores. Although many of the biochemical events involved in the apoptotic process are Ca2+ dependent, the exact mechanism by wh ich Ca2+ triggers apoptosis remains unknown. The bcl-2 gene family, wh ich includes both inhibitors and inducers of apoptosis, appears to reg ulate intracellular Ca2+ compartmentalization. The induction of apopto sis by Ca2+ -mobilizing agents results in caspase activation, which is similar to what is seen with other inducers of apoptosis. In addition , Ca2+-dependent proteases, such as calpain and a Ca2+-dependent nucle ar scaffold-associated serine protease, are also activated by Ca2+ sig nalling in some cell types where they appear to be involved in alpha-f odrin and lamin beta cleavage, respectively. Thus, a spectrum of prote ases are activated during apoptosis depending on both cell type and in ducer. This proteolytic cascade can involve both caspases and Ca2+-dep endent proteases, which seem to interact during the apoptotic process. (C) 1998 Elsevier Science Ltd. All rights reserved.