Regulation of inositol 1,4,5-trisphosphate receptors during endoplasmic reticulum stress

Abstract

The endoplasmic reticulum (ER) performs multiple functions in the cell: it is the major site of protein and lipid synthesis as well as the most important intracellular Ca(2+) reservoir. Adverse conditions, including a decrease in the ER Ca(2+) level or an increase in oxidative stress, impair the formation of new proteins, resulting in ER stress. The subsequent unfolded protein response (UPR) is a cellular attempt to lower the burden on the ER and to restore ER homeostasis by imposing a general arrest in protein synthesis, upregulating chaperone proteins and degrading misfolded proteins. This response can also lead to autophagy and, if the stress can not be alleviated, to apoptosis. The inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) and IP3-induced Ca(2+) signaling are important players in these processes. Not only is the IP3R activity modulated in a dual way during ER stress, but also other key proteins involved in Ca(2+) signaling are modulated. Changes also occur at the structural level with a strengthening of the contacts between the ER and the mitochondria, which are important determinants of mitochondrial Ca(2+) uptake. The resulting cytoplasmic and mitochondrial Ca(2+) signals will control cellular decisions that either promote cell survival or cause their elimination via apoptosis. This article is part of a Special Issue entitled: 12th European Symposium on Calcium.

Asbestos-induced Disruption of Calcium Homeostasis Induces Endoplasmic Reticulum Stress in Macrophages

“…Oxidative stress can trigger ER stress and promote ER Ca 2ϩ release (18), perhaps by inhibiting ER Ca 2ϩ -ATPase activity (37). Alternatively, IP 3 R is an IP 3 -gated channel that releases Ca 2ϩ from the ER and is activated by IP 3 , Ca 2ϩ , and oxidative stress (30). We found that knockdown of IP 3 R-1 did not alter chrysotile-induced increases in cytosolic Ca 2ϩ ; however, our Ca 2ϩ measurements were obtained from a population of cells, which may not provide the resolution necessary for detecting changes in Ca 2ϩ within a single cell or within mitochondria (31,38).…”

Redox controls UPR to control redox

“…upregulation of Ero1a potentiates IP 3 -induced Ca 2+ release (Anelli et al, 2012;Kiviluoto et al, 2013;Li et al, 2009). Furthermore, the degradation of IP 3 Rs and RyRs is inhibited during ER stress (Belal et al, 2012) and the ER membrane protein s-1 receptor dissociates from BiP to chaperone and stabilize type 3 IP 3 R at MAM (Hayashi and Su, 2007).…”

“…following disturbed lipid metabolism, glucose starvation or inflammatory mediators, is a well-known phenomenon during ER-stress-dependent toxicity (Cardozo et al, 2005;Fu et al, 2011;Hara et al, 2014;Moore et al, 2011). Likewise, altered IP 3 R activity and increases in passive Ca 2+ leak from the ER are hallmarks of ER-stressed cells (Kiviluoto et al, 2013) (see also below).…”

Bcl-2 binds to and inhibits ryanodine receptors

“…Therefore, the function of Bcl-2 in cells seems to be tightly linked to its ability to modulate intracellular Ca 2+ homeostasis and dynamics. This is important, given the central role of both Bcl-2 and of Ca 2+ signaling in cell-fate decisions, mitochondrial bioenergetics, autophagy, ER stress and apoptosis (Chipuk et al, 2010;Giorgi et al, 2008;Kiviluoto et al, 2013). Recent evidence indicates that the regulation of intracellular Ca 2+ handling by Bcl-2-family proteins is also important for non-apoptotic functions, including neuroplasticity, cellular migration, cell cycle regulation and embryonic development (Bonneau et al, 2013).…”