1. A peptide inhibitor of cytochrome c/inositol 1,4,5-trisphosphate receptor binding blocks intrinsic and extrinsic cell death pathways.
- Author
-
Boehning D, van Rossum DB, Patterson RL, and Snyder SH
- Subjects
- Amino Acid Sequence, Animals, Apoptosis drug effects, Calcium Signaling physiology, Cloning, Molecular, Cytochromes c antagonists & inhibitors, Endoplasmic Reticulum drug effects, Endoplasmic Reticulum physiology, Humans, Inositol 1,4,5-Trisphosphate Receptors, Jurkat Cells, Kinetics, Microscopy, Confocal, Molecular Sequence Data, Peptides chemistry, Peptides pharmacology, Rats, Receptors, Cytoplasmic and Nuclear antagonists & inhibitors, Staurosporine pharmacology, Calcium Channels physiology, Cell Death drug effects, Cytochromes c metabolism, Receptors, Cytoplasmic and Nuclear physiology
- Abstract
Apoptotic stimuli augment intracellular calcium concentration through inositol 1,4,5-trisphosphate receptors (IP3R) on endoplasmic reticulum calcium stores. We previously discovered an apoptotic cascade wherein cytochrome c binds to IP3R early in apoptosis, resulting in dysregulated calcium release. Here we show that cytochrome c binding to IP3R depends on a cluster of glutamic acid residues within the C terminus of the channel. A cell permeant peptide derived from this sequence displaces cytochrome c from IP3R and abrogates cell death induced by staurosporine treatment of HeLa cells and Fas ligand stimulation of Jurkat cells. Small-molecule inhibitors of cytochrome c/IP3R interactions may prove useful in treating disorders associated with inappropriate intrinsic and extrinsic apoptotic signaling.
- Published
- 2005
- Full Text
- View/download PDF