![]() SERCA-dependent Ca 2+ influx is counterbalanced by a basal Ca 2+ leakage and the opening of various second messenger gated channels activated by different extracellular stimuli. The ER lumen serves as the main source of releasable Ca 2+ for cytosolic signaling, which is maintained by the Sarcoplasmic/Endoplasmic Reticulum Calcium ATP-ase (SERCA) pump. Unresolved ER stress can finally result in programmed cell death. ER stress triggers an adaptive program of signal transduction pathways, called the Unfolded Protein Response (UPR). Either the depletion of luminal Ca 2+ or the alteration of the redox balance can lead to ER stress that is an ominous accumulation of unfolded proteins in the ER lumen. Proper maintenance of the intraluminal homeostasis in the ER is a vital requirement for the cell. Its content resembles that of an “extracellular space inside the cell.” For example, it is characterized by a high Ca 2+ concentration and an oxidizing redox balance, whereas the term “redox balance” shall herein refer to the thiol/disulfide system only. The lumen of the endoplasmic reticulum (ER) is the first compartment of the eukaryotic secretory pathway. These findings have important implications for ER redox homeostasis under normal physiology and ER stress. We postulate the existence of a Ca 2+- and cyclosporine A-sensitive GSH transporter in the ER membrane. Our data strongly suggest that ER influx of cytosolic GSH, rather than inhibition of local oxidoreductases, is responsible for the reductive shift upon Ca 2+ mobilization. While the action of puromycin was ascribable to Ca 2+ leakage from the ER, the mechanism of cyclosporine A-induced GSH flux was independent of calcineurin and cyclophilins A and B and remained unclear. However, opening the translocon channel by puromycin or addition of cyclosporine A mimicked the GSH-related effect of Ca 2+ mobilization. Inducible reduction of the ER lumen by GSH flux was independent of the Ca 2+-binding chaperone calreticulin, which has previously been implicated in this process. A glutathione-centered mechanism was further indicated by increased ER luminal glutathione levels in response to Ca 2+ efflux. We found that Ca 2+ mobilization-dependent ER luminal reduction was sensitive to inhibition of GSH synthesis or dilution of cytosolic GSH by selective permeabilization of the plasma membrane. Although depletion of luminal Ca 2+ from the ER provokes a rapid and reversible shift towards a more reducing poise in the ER, the underlying molecular basis remains unclear. The lumen of the endoplasmic reticulum (ER) acts as a cellular Ca 2+ store and a site for oxidative protein folding, which is controlled by the reduced glutathione (GSH) and glutathione-disulfide (GSSG) redox pair.
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