Regulation of calcium homeostasis and flux between the endoplasmic reticulum and the cytosol.

The concentration of Ca in the endoplasmic reticulum (ER) is critically important for maintaining its oxidizing environment as well as for maintaining luminal ATP levels required for chaperone activity. Therefore, local luminal Ca concentrations and the dynamic Ca flux between the different subcellular compartments are tightly controlled. Influx of Ca into the ER is enabled by a reductive shift, which opens the sarcoendoplasmic reticulum calcium transport ATPase pump, building the Ca gradient across the ER membrane required for ATP import. Meanwhile, Ca leakage from the ER has been reported to occur via the Sec61 translocon following protein translocation. In this review, we provide an overview of the complex regulation of Ca homeostasis, Ca flux between subcellular compartments, and the cellular stress response (the unfolded protein response) induced upon dysregulated luminal Ca metabolism. We also provide insight into the structure and gating mechanism at the Sec61 translocon and examine the role of ER-resident cochaperones in assisting the central ER-resident chaperone BiP in the control of luminal Ca concentrations.