Calcium signaling and cytotoxicity.

Abstract

The divalent calcium cation Ca(2+) is used as a major signaling molecule during cell signal transduction to regulate energy output, cellular metabolism, and phenotype. The basis to the signaling role of Ca(2+) is an intricate network of cellular channels and transporters that allow a low resting concentration of Ca(2+) in the cytosol of the cell ([Ca(2+)]i) but that are also coupled to major dynamic and rapidly exchanging stores. This enables extracellular signals from hormones and growth factors to be transduced as [Ca(2+)]i spikes that are amplitude and frequency encoded. There is considerable evidence that a number of toxic environmental chemicals target these Ca(2+) signaling processes, alter them, and induce cell death by apoptosis. Two major pathways for apoptosis will be considered. The first one involves Ca(2+)-mediated expression of ligands that bind to and activate death receptors such as CD95 (Fas, APO-1). In the second pathway, Ca(2+) has a direct toxic effect and its primary targets include the mitochondria and the endoplasmic reticulum (ER). Mitochondria may respond to an apoptotic Ca(2+) signal by the selective release of cytochrome c or through enhanced production of reactive oxygen species and opening of an inner mitochondrial membrane pore. Toxic agents such as the environmental pollutant tributyltin or the natural plant product thapsigargin, which deplete the ER Ca(2+) stores, will induce as a direct result of this effect the opening of plasma membrane Ca(2+) channels and an ER stress response. In contrast, under some conditions, Ca(2+) signals may be cytoprotective and antagonize the apoptotic machinery.ImagesFigure 1Figure 2Figure 3

Salt stress-induced programmed cell death via Ca2+-mediated mitochondrial permeability transition in tobacco protoplasts

“…However, in animals, many results indicate that an increased [Ca 2+ ] cyt does not always induce cell death, on some occasions it can inhibit apoptosis, there are also data which indicate that a decrease in Ca 2+ can also induce apoptosis (Kass and Orrenius 1999). In the present study, we have investigated whether intracellular Ca 2+ accumulation regulates cell death in tobacco protoplasts under NaCl stress.…”

Chelation of Extracellular Calcium-Induced Cell Death was Prevented by Glycogen Synthase Kinase-3 Inhibitors in PC12 Cells

“…storage protein, with approximately 25% of the ER Ca 2? store being bound to this protein (Kass and Orrenius 1999;Lievremont et al 1997). Several transmembrane proteins in the ER have been identified as sensors of ER stress.…”

Bcl-2 decreases the free Ca 2+ concentration within the endoplasmic reticulum

“…TG-induced massive Ca 2ϩ store depletion may induce cell death (47). However, recent results suggest that Ca 2ϩ stored within the ER may also be the cause of apoptosis, as it is the source for Ins(1,4,5)P 3 -dependent Ca 2ϩ spikes which lead to Ca 2ϩ -dependent activation of the mitochondrial transition pore (39 influx (48,49), the Bcl-2-induced increase in unstimulated Ca 2ϩ influx and elevation of basal [Ca 2ϩ ] c (Fig. 7) are good candidates to be involved in its antiapoptotic activity.…”