Cytochrome c binds to inositol (1,4,5) trisphosphate receptors, amplifying calcium-dependent apoptosis

  title={Cytochrome c binds to inositol (1,4,5) trisphosphate receptors, amplifying calcium-dependent apoptosis},
  author={Darren Boehning and Randen L. Patterson and Leela Sedaghat and Natalia O. Glebova and Tomohiro Kurosaki and Solomon H. Snyder},
  journal={Nature Cell Biology},
Mitochondrial 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… 

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

It is shown that cytochrome c binding to IP3R depends on a cluster of glutamic acid residues within the C terminus of the channel, which may prove useful in treating disorders associated with inappropriate intrinsic and extrinsic apoptotic signaling.

Inositol 1,4,5-trisphosphate receptor/GAPDH complex augments Ca2+ release via locally derived NADH.

The selective binding of IP3R to GAPDH, whose activity leads to the local generation of NADH to regulate intracellular calcium signaling, likely enables cellular energy dynamics to impact calcium signaling.

Cytochrome c: A Crosslink between the Mitochondria and the Endoplasmic Reticulum in Calcium-Dependent Apoptosis

It is reported that early in apoptosis mitochondrial cyctochrome c translocates to the endoplasmic reticulum where it specifically binds inositol (1,4,5) triphosphate receptors, leading to sustained calcium release, thus amplifying the apoptotic signal.

Bcl-2 functionally interacts with inositol 1,4,5-trisphosphate receptors to regulate calcium release from the ER in response to inositol 1,4,5-trisphosphate

The anti-apoptotic protein Bcl-2 significantly inhibited InsP3-mediated calcium release and elevation of cytosolic calcium in WEHI7.2 T cells because responses to both anti-CD3 antibody and a cell-permeant InsP 3 ester were decreased.

IP3 receptors in cell survival and apoptosis: Ca2+ release and beyond

The role of IP3Rs in delivering Ca2+ to the mitochondria is discussed from the perspective of the factors determining inter-organellar dynamics and the spatial proximity of mitochondria and ER membranes.

Proteolytic fragmentation of inositol 1,4,5‐trisphosphate receptors: a novel mechanism regulating channel activity?

It is proposed that cleavage of the IP3R peptide chain may alter other important regulatory events to modulate channel activity and speculate that proteolytic fragmentation may represent a novel form ofIP3R regulation, which plays a role in varied adaptive physiological processes.

Requirement of biphasic calcium release from the endoplasmic reticulum for Fas-mediated apoptosis

It is shown that Fas-mediated apoptosis requires endoplasmic reticulum–mediated calcium release in a mechanism dependent on phospholipase C-γ1 activation and Ca2+ release from inositol 1,4,5-trisphosphate receptor (IP3R) channels.

RACK1 binds to inositol 1,4,5-trisphosphate receptors and mediates Ca2+ release.

These findings establish RACK1 as a physiologic mediator of agonist-induced Ca2+ release.



Calcium as a coagonist of inositol 1,4,5-trisphosphate-induced calcium release.

Inositol 1,4,5-trisphosphate (IP3)-induced calcium release from intracellular stores is a regulator of cytosolic-free calcium levels. The subsecond kinetics and regulation of IP3-induced calcium-45

T cells deficient in inositol 1,4,5-trisphosphate receptor are resistant to apoptosis

It is shown that IP3R1-deficient T cells are resistant to apoptosis induced by dexamethasone, TCR stimulation, ionizing radiation, and Fas, indicating that extracellular calcium influx is not required.

Control of apoptosis by IP(3) and ryanodine receptor driven calcium signals.

This article will focus on the IP(3)R/RyR-dependent pathways to apoptosis, particularly on the mitochondrial phase of the death cascade, and the functional importance of these mitochondrial calcium signalling pathways has been underscored by the elucidation of a highly effective, local Ca(2+)coupling between IP( 3)R/.

Type 3 inositol 1,4,5‐trisphosphate receptor modulates cell death

Type 3 inositol 1,4,5‐trisphosphate receptor modulates cell death and appears to participate actively in cell death in a diversity of tissues.

The coordinate release of cytochrome c during apoptosis is rapid, complete and kinetically invariant

It is found that the electron-transport chain can maintain the mitochondrial transmembrane potential even after cytochrome c has been released, and the addition of caspase inhibitors does not change the duration of release.

Endoplasmic reticulum, Bcl-2 and Ca2+ handling in apoptosis.

Lymphocyte Apoptosis: Mediation by Increased Type 3 Inositol 1,4,5-Trisphosphate Receptor

B and T lymphocytes undergoing apoptosis in response to anti-immunoglobulin M antibodies and dexamethasone, respectively, were found to have increased amounts of messenger RNA for the inositol

Quantal calcium release by purified reconstituted inositol 1,4,5-trisphosphate receptors

It is shown here that quantal flux of Ca2+ elicited by InsP3 is a fundamental property of its receptor, and reconstituted vesicles containing only purified InsP 3 receptor protein retain the regulatory features of the InsP2 receptor.

Inositol 1,4,5-Trisphosphate Receptor Type 1 Is a Substrate for Caspase-3 and Is Cleaved during Apoptosis in a Caspase-3-dependent Manner*

The cleavage of IP3R1 during apoptosis in the MCF-7 breast carcinoma cell line, which has genetically lost caspase-3, was found to be cleaved and resulted in a decrease in the channel activity as IP2R1 was digested, indicating that casp enzyme-3 inactivates IP1R1 channel functions.

Selective down-regulation of IP(3)receptor subtypes by caspases and calpain during TNF alpha -induced apoptosis of human T-lymphoma cells.

It is proposed that the selective down-regulation of IP(3)R subtype-mediated Ca(2+)function by caspase-dependent and calpain-sensitive mechanisms may be responsible for the early onset of the apoptotic signal by TNFalpha in human T-cells.