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PMID: 15665074 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

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

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 102 ·No. 5 ·2005-02-01 ·Pages 1466-71

Boehning D, van Rossum DB, Patterson RL, Snyder SH

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.

MeSH Terms
Amino Acid Sequence Animals Apoptosis/drug effects Calcium Channels/physiology Calcium Signaling/physiology Cell Death/drug effects Cloning, Molecular Cytochromes c/antagonists & inhibitors,metabolism Endoplasmic Reticulum/drug effects,physiology Humans Inositol 1,4,5-Trisphosphate Receptors Jurkat Cells Kinetics Microscopy, Confocal Molecular Sequence Data Peptides/chemistry,pharmacology Rats Receptors, Cytoplasmic and Nuclear/antagonists & inhibitors,physiology Staurosporine/pharmacology
Chemicals
Calcium Channels ITPR1 protein, human Inositol 1,4,5-Trisphosphate Receptors Peptides Receptors, Cytoplasmic and Nuclear Cytochromes c Staurosporine
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Boehning Darren
Department of Neuroscience, The Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA.
van Rossum Damian B
Patterson Randen L
Snyder Solomon H
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.0409650102
Published
2005-02-01
Epub
2005-00-21
Pages
1466-71
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC547891
Subset
IM
Grants
NIDA NIH HHS · DA-000266 · United States
NINDS NIH HHS · F32 NS043850 · United States
NIMH NIH HHS · R37 MH018501 · United States
NIMH NIH HHS · R01 MH018501 · United States
NIDA NIH HHS · DA-00074 · United States
NIDA NIH HHS · P50 DA000266 · United States
NIDA NIH HHS · K05 DA000074 · United States
NIMH NIH HHS · MH-18501 · United States
NIH HHS · NH65090 · United States
NINDS NIH HHS · NS-043850 · United States
External Links
PubMed source DOI: 10.1073/pnas.0409650102 PMC Full Text View journal details
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