Nature Cell Biology
5, 1051 - 1061 (2003)
Published online: 9 November 2003; | doi:10.1038/ncb1063
There is an Erratum (January 2004) associated with this Article.
Cytochrome c binds to inositol (1,4,5) trisphosphate receptors, amplifying calcium-dependent apoptosisDarren Boehning1, 5, Randen L. Patterson1, 5, Leela Sedaghat1, Natalia O. Glebova1, Tomohiro Kurosaki4
& Solomon H. Snyder1, 2, 31
Department of Neuroscience, Johns Hopkins University School of Medicine, 725 N. Wolfe Street, Baltimore, Maryland 21205, USA. 2
Departments of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, 725 N. Wolfe Street, Baltimore, Maryland 21205, USA. 3
Departments of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 725 N. Wolfe Street, Baltimore, Maryland 21205, USA. 4
Department of Molecular Genetics, Institute for Liver Research, Kansai Medical University, and Laboratory for Lymphocyte Differentiation, RIKEN Research Center for Allergy and Immunology, Moriguchi 570-8506, Japan. 5
These authors contributed equally to this work.
Correspondence should be addressed to Solomon H. Snyder ssnyder@jhmi.eduMitochondrial cytochrome c release and inositol (1,4,5) trisphosphate receptor (InsP3R)-mediated calcium release from the endoplasmic reticulum mediate apoptosis in response to specific stimuli. Here we show that cytochrome c binds to the InsP3R during apoptosis. Addition of 1 nM cytochrome c blocks calcium-dependent inhibition of InsP3R function. Early in apoptosis, cytochrome c translocates to the endoplasmic reticulum where it selectively binds InsP3R, resulting in sustained, oscillatory cytosolic calcium increases. These calcium events are linked to the coordinate release of cytochrome c from all mitochondria. Our findings identify a feed-forward mechanism whereby early cytochrome c release increases InsP3R function, resulting in augmented cytochrome c release that amplifies the apoptotic signal.
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