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

The concentration of Ca(2+) 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(2+) concentrations and the dynamic Ca(2+) flux between the different subcellular compartments are tightly controlled. Influx of Ca(2+) into the ER is enabled by a reductive shift, which opens the sarcoendoplasmic reticulum calcium transport ATPase pump, building the Ca(2+) gradient across the ER membrane required for ATP import. Meanwhile, Ca(2+) 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(2+) homeostasis, Ca(2+) flux between subcellular compartments, and the cellular stress response (the unfolded protein response) induced upon dysregulated luminal Ca(2+) 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(2+) concentrations.