Isoform- and species-specific control of inositol 1,4,5-trisphosphate (IP3) receptors by reactive oxygen species.

Authors

Száva Bánsághi, Thomas Jefferson UniversityFollow
Tünde Golenár, Thomas Jefferson UniversityFollow
Muniswamy Madesh, Thomas Jefferson UniversityFollow
György Csordás, Thomas Jefferson UniversityFollow
Satish P. RamachandraRao, Thomas Jefferson UniversityFollow
Kumar Sharma, Thomas Jefferson UniversityFollow
David I Yule, University of Rochester Medical Center
Suresh K Joseph, Thomas Jefferson UniversityFollow
György Hajnóczky, Thomas Jefferson UniversityFollow

Document Type

Article

Publication Date

3-21-2014

Comments

This article has been peer reviewed. It is the authors' final version prior to publication in Journal of Biological Chemistry

Volume 289, Issue 12, March 2014, Pages 8170-8181.

The published version is available at DOI: 10.1074/jbc.M113.504159. Copyright © American Society for Biochemistry and Molecular Biology Inc.

Abstract

Reactive oxygen species (ROS) stimulate cytoplasmic [Ca(2+)] ([Ca(2+)]c) signaling, but the exact role of the IP3 receptors (IP3R) in this process remains unclear. IP3Rs serve as a potential target of ROS produced by both ER and mitochondrial enzymes, which might locally expose IP3Rs at the ER-mitochondrial associations. Also, IP3Rs contain multiple reactive thiols, common molecular targets of ROS. Therefore, we have examined the effect of superoxide anion (O2) on IP3R-mediated Ca(2+) signaling. In human HepG2, rat RBL-2H3, and chicken DT40 cells, we observed [Ca(2+)]c spikes and frequency-modulated oscillations evoked by a O2 donor, xanthine (X) + xanthine oxidase (XO), dose-dependently. The [Ca(2+)]c signal was mediated by ER Ca(2+) mobilization. X+XO added to permeabilized cells promoted the [Ca(2+)]c rise evoked by submaximal doses of IP3, indicating that O2 directly sensitizes IP3R-mediated Ca(2+) release. In response to X+XO, DT40 cells lacking two of three IP3R isoforms (DKO) expressing either type 1 (DKO1) or type 2 IP3Rs (DKO2) showed a [Ca(2+)]c signal, whereas DKO expressing type 3 IP3R (DKO3) did not. By contrast, IgM that stimulates IP3 formation, elicited a [Ca(2+)]c signal in every DKO. X+XO also facilitated the Ca(2+) release evoked by submaximal IP3 in permeabilized DKO1 and DKO2 but was ineffective in DKO3 or in DT40 lacking every IP3R (TKO). However, X+XO could also facilitate the effect of suboptimal IP3 in TKO transfected with rat IP3R3. Although in silico studies failed to identify a thiol missing in the chicken IP3R3, an X+XO-induced redox change was documented only in the rat IP3R3. Thus, ROS seem to specifically sensitize IP3Rs through a thiol group(s) within the IP3R, which is probably inaccessible in the chicken IP3R3.

Recommended Citation

Bánsághi, Száva; Golenár, Tünde; Madesh, Muniswamy; Csordás, György; RamachandraRao, Satish P.; Sharma, Kumar; Yule, David I; Joseph, Suresh K; and Hajnóczky, György, "Isoform- and species-specific control of inositol 1,4,5-trisphosphate (IP3) receptors by reactive oxygen species." (2014). Department of Pathology, Anatomy, and Cell Biology Faculty Papers. Paper 158.
https://jdc.jefferson.edu/pacbfp/158

PubMed ID

24469450