Control of apoptosis by IP₃ and ryanodine receptor driven calcium signals

Intracellular calcium signals mediated by IP₃ and ryanodine receptors (IP₃R/RyR) play a central role in cell survival, but emerging evidence suggests that IP₃R/RyR are also important in apoptotic cell death. Switch from the life program to the death program may involve coincident detection of proapoptotic stimuli and calcium signals or changes in the spatiotemporal pattern of the calcium signal or changes at the level of effectors activated by the calcium signal (e.g. calpain, calcineurin). The fate of the cell is often determined in the mitochondria, where calcium spikes may support cell survival through stimulation of ATP production or initiate apoptosis via opening of the permeability transition pore and release of apoptotic factors such as cytochrome c. The functional importance of these mitochondrial calcium signalling pathways has been underscored by the elucidation of a highly effective, local Ca²⁺ coupling between IP₃R/RyR and mitochondrial Ca²⁺ uptake sites. This article will focus on the IP₃R/RyR-dependent pathways to apoptosis, particularly on the mitochondrial phase of the death cascade.