Regulation of the endoplasmic reticulum calcium storage during the unfolded protein response - Significance in tissue ischemia?

Endoplasmic reticulum (ER) is an organelle intimately involved in control of cell activities through Ca2+ signaling, as well as in post-translational protein folding and maturation. Ca2+ storage within the ER is required for both of these functions. Several of the ER-resident proteins essential for the protein folding pathway require Ca2+ binding for their activity. A number of factors, including Ca2+ depletion, may interfere with the folding pathway within the ER, with a potential for cell injury through an accumulation of malfolded protein aggregates. The Unfolded Protein Response involves a transcriptional upregulation of a number of the ER-resident folding helper proteins and becomes triggered when the folding pathway is blocked. To be effective, these upregulated proteins require a sufficient Supply Of Ca2+ cofactor within the ER lumen. In tissue ischemia, where the availability of this cofactor may be compromised, the newly described ability of the cell to boost the ER Ca2+-loading capacity by upregulating the ER Ca2+ pump may be of particular importance for limiting cell injury and promoting survival. The novel focus on the pathophysiological significance of ER Ca2+ depletion extends the scope of disturbed Ca2+ homeostasis following ischemia beyond the consequences of the cytosolic calcium overload. (Trends Cardiovasc Med 2002; 12:57-62). (C) 2002, Elsevier Science Inc.