Apoptosis and calcium: new roles for cytochrome c and inositol 1,4,5-trisphosphate.
Mounting evidence suggests that calcium released from internal stores plays a critical role in the progression of apoptosis. The primary calcium release channel on endoplasmic reticulum membranes is the inositol 1,4,5-trisphosphate receptor (IP3R). Deletion of the gene for IP3R results in defects in apoptosis in response to multiple stimuli. Conversely, augmented IP3R levels are associated with increased cell death. A mechanistic basis for altered IP3R function during apoptosis was revealed with the discovery that cytochrome c binds to IP3R early in apoptosis. This interaction blocks the calcium-dependent inhibition of IP3R function, resulting in increased calcium release from internal stores. The resultant cytoplasmic and mitochondrial calcium overload culminates in cell-wide cytochrome c release and maximal caspase activation. These findings highlight the importance of intracellular calcium stores in apoptosis, and the multi-functional role of cytochrome c released from mitochondria in cell death.
Boehning
Darren
D
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Patterson
Randen L
RL
Snyder
Solomon H
SH
D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism*; D045304:Cytochromes c / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism
D015544:Inositol 1,4,5-Trisphosphate; D045304:Cytochromes c; D002118:Calcium