Ca2+ in Apoptosis

The role of intracellular free calcium in cell death has been highly controversial. Alteration of the intracellular Ca2+ concentration, [Ca2+]i, can lead to cell death. Death can be induced when Ca2+ gains entry from the extracellular medium via the plasma membrane after treatment with Ca2+ ionophores or is mobilized from the ER using thapsigargin, an inhibitor of the specific ER calcium pump. Buffering of intracellular free calcium can, in some cases, inhibit cell death.

Elevated [Ca2+]i concentrations are recognized as a key factor in necrosis, whereas a more variegated relationship has emerged between [Ca2+]i and apoptosis. As extracellular [Ca2+] typically exceed intracellular [Ca2+] by four orders of magnitude, a large increase in Ca2+ influx and [Ca2+]i inevitably accompanies the collapse of the plasma membrane that occurs early in necrosis. There are many reasons why large elevations in [Ca2+]i are cytotoxic, including a subsequent derangement in signaling and mitochondrial function as well as the destruction of cellular components by Ca2+-activated catabolic enzymes and free radicals.

Less dramatic elevations in [Ca2+]i may also mediate apoptosis. Such elevations occur in synovial cells, lymphocytes, prostate cells and neurons undergoing apoptosis, both at early stages (minutes-hours) and late steps (post commitment point). Possible targets of a late rise in [Ca2+]i during apoptosis include key Ca2+-activated proteases and endonucleases such as NUC18, as well as possibly caspase-3-like caspases. Ca2+ released from cellular stores may trigger apoptosis owing to their proximity to mitochondria resulting in mitochondrial Ca2+ uptake and consequent overload, triggering PT pore opening and cytoc release (Hajnoczky et al., 2000, calcium, 28: 349-363). In addition, Ca2+ depletion from the ER may impair protein synthesis.

Still, the links between elevated [Ca2+]i and apoptosis are controversial. Not all dying cells exhibit elevations in [Ca2+]i prior to final membrane failure. Also, lowering of extracellular [Ca2+] or blocking membrane Ca2+ channels can itself trigger apoptosis in vitro or enhance pathological neuronal apoptosis in vivo. Additionally, modestly elevating [Ca2+]i can inhibit apoptosis. This might be explained since [Ca2+]i mediated multiple signalling cascades that are critical for cell survival, including Ca2+/calmodulin- dependent protein kinases kinase, protein kinase B and the phosphorylation of BAD.

See the review by Ping Yu et al., 2001, Curr Op. Cell Biol., 13:405-11.