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PNAS 102 (5): 1466-1471

Copyright © 2005 by the National Academy of Sciences.


CELL BIOLOGY

A peptide inhibitor of cytochrome c/inositol 1,4,5-trisphosphate receptor binding blocks intrinsic and extrinsic cell death pathways

Darren Boehning *, Damian B. van Rossum *, Randen L. Patterson *, and Solomon H. Snyder *, {dagger}, {ddagger}, §

Departments of *Neuroscience, {dagger}Pharmacology and Molecular Sciences, and {ddagger}Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205

Contributed by Solomon H. Snyder, December 22, 2004

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.

Key Words: apoptosis • calcium • Fas • caspase • T lymphoma


Abbreviations: STS, staurosporine; IP3R, inositol 1,4,5-trisphosphate receptor; FasL, Fas ligand; HA, hemagglutinin.

§ To whom correspondence should be addressed at: Department of Neuroscience, The Johns Hopkins University, 725 North Wolfe Street, 813 WBSB, Baltimore, MD 21205. E-mail: ssnyder{at}jhmi.edu.

© 2005 by The National Academy of Sciences of the USA


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