IP3 receptors in cell survival and apoptosis: Ca2+ release and beyond.

Inositol 1,4,5-trisphosphate receptors (IP(3)Rs) serve to discharge Ca(2+) from ER stores in response to agonist stimulation. The present review summarizes the role of these receptors in models of Ca(2+)-dependent apoptosis. In particular we focus on the regulation of IP(3)Rs by caspase-3 cleavage, cytochrome c, anti-apoptotic proteins and Akt kinase. We also address the evidence that some of the effects of IP(3)Rs in apoptosis may be independent of their ion-channel function. The role of IP(3)Rs in delivering Ca(2+) to the mitochondria is discussed from the perspective of the factors determining inter-organellar dynamics and the spatial proximity of mitochondria and ER membranes.