Calcium Signaling and Cytotoxicity

Abstract

The divalent calcium cation Ca2+ 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 Ca2+ is an intricate network of cellular channels and transporters that allow a low resting concentration of Ca2+ in the cytosol of the cell (lCa2+1) 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 ICa2+li spikes that are amplitude and frequency encoded. There is considerable evidence that a number of toxic environmental chemicals target these Ca2+ signaling processes, alter them, and induce cell death by apoptosis. Two major pathways for apoptosis will be considered. The first one involves Ca2+-mediated expression of ligands that bind to and activate death receptors such as CD95 (Fas, APO-1). In the second pathway, Ca2+ has a direct toxic effect and its primary targets include the mitochondria and the endoplasmic reticulum (ER). Mitochondria may respond to an apoptotic Ca2+ 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 Ca2+ stores, will induce as a direct result of this effect the opening of plasma membrane Ca2+ channels and an ER stress response. In contrast, under some conditions, Ca2+ signals may be cytoprotective and antagonize the apoptotic machinery. -Environ Health Perspect 1 07(Suppl 1 ): 25-35 (1999). http://ehpnet1.niehs.nih.gov/docs/1999/Suppl-1/25-35kass/abstracthtml

Static magnetic fields affect calcium fluxes and inhibit stress‐induced apoptosis in human glioblastoma cells

“…It will be interesting to investigate the route of Ca 2ϩ entry for these phenomena. We previously demonstrated that in U937 cells MFs increase cell survival from damaging agents via increased Ca 2ϩ influx because MFs failed to exert their anti-apop- (24). This apparent paradox might be explained by considering the role played in apoptosis by the endoplasmic reticulum, the main intracellular Ca 2ϩ store whose integrity is maintained by a proper intralumenal Ca 2ϩ concentration.…”

Role of intracellular calcium and phospholipase A2 in arachidonic acid-induced toxicity in liver cells overexpressing CYP2E1

“…These include oxidative metabolism of AA to biologically active eicosanoids and/or reactive oxygen species [8,9,14], induction of the mitochondrial permeability transition [13,17], accumulation of cellular ceramides [10,11] and intracellular calcium regulation [12]. An increase of intracellular calcium may aggravate the mechanism of cell injury and accelerate the time of onset of the mitochondrial permeability transition [18,19], and activate Ca 2+ -dependent hydrolases such as calpain and phospholipase A2 [20]. The role of calcium in AA-induced cytotoxicity seems to depend on the experimental model under study, as increased release of calcium from intracellular stores was related to AA-dependent cell death in a neuronal cell line [12], but Ca 2+ influx was not involved in AA toxicity in PC12 cells [16].…”

Role of Calcium and Calcium-activated Proteases in CYP2E1-dependent Toxicity in HEPG2 Cells

“…Although intracellular calcium has been suggested to play a role in the oxidative damage of hepatocytes, the effects and source of the oxidative stress-induced intracellular Ca 2ϩ increase are currently debatable (6). Treatment of liver cells with several oxidative stress inducer drugs increases [Ca 2ϩ ] i and produces cell toxicity through necrosis and/or apoptosis, depending on the degree of exposure (dose and duration) (2). The initial source of Ca 2ϩ depends on the specific oxidant and cell type employed, since certain toxins cause calcium release from intracellular stores (5, 7), whereas others cause Ca 2ϩ influx from the extracellular space (6,8).…”

“…According to the calcium hypothesis of cell injury, a perturbation of intracellular Ca 2ϩ homeostasis leading to a sustained increase in cytosolic Ca 2ϩ is an early and critical event in the development of toxicity in hepatocytes exposed to oxidative stress, causing the ultimate loss of cell viability through activation of various Ca 2ϩ -dependent processes (1,2). Increases of [Ca 2ϩ ] i can result from an influx of Ca 2ϩ from the extracellular medium, redistribution of Ca 2ϩ from intracellular stores, or both influx and redistribution.…”