Figure 1. Ca²⁺ homeostasis in the ER.

Right: tool-kit of Ca²⁺ handling proteins. Ligand binding of GPCRs leads to the biosynthesis of the intracellular messengers such as IP3, which diffuses into the cell and binds to IP3R, stimulating Ca²⁺ release from the ER. Ca²⁺ channels activated by IP3 release Ca²⁺ from ER to the cytosol. RyR also releases Ca²⁺ from ER to the cytosol. SERCA (Ca²⁺-ATPase) pumps Ca²⁺ from cytosol to the ER lumen at the expense of ATP hydrolysis. STIM is an ER membrane protein that possesses 2 EF hand domains. Under basal conditions, Ca²⁺ is bound to these domains and the protein remains in its monomeric form. After Ca²⁺ release from ER, Ca²⁺ dissociates from the of STIM proteins leading to oligomerization and trafficking of STIM through the ER membrane toward the plasma membrane contact sites. This localization, allows STIM to couple with the plasma membrane Ca²⁺ channel Orai and Ca²⁺ enters the cell from the extracellular space, a process known as capacitive or store operator Ca²⁺ entry (SOCE). SERCA colocalizes with STIM/Orai complex, and is thought to pump Ca²⁺ directly from cytosol to ER lumen. Left: ER protein folding machinery: During glycoprotein biosynthesis, the translation of nascent polypeptides is followed by their translocation of the peptides through the SEC61 pore. Sugar molecules are added to the polypeptides that are recognized by lectin chaperones such as calnexin (CNX) and calretculin (CRT), which function in complex with ERp57 and ERp72. Additional chaperone assistance is provided by the ATP-driven chaperone BiP (GRP78). Calnexin and calreticulin also bind Ca²⁺ with high capacity, functioning as the main Ca²⁺ buffers in the ER lumen. Ca²⁺ depletion leads to accumulation of misfolded proteins and the activation of the unfolded protein response (UPR), mediated by three canonical ER luminal sensors, IRE1, PERK, and ATF6, which are inactive and bound to BiP in the absence of stress. GPCR: G protein–coupled receptor. IP3: inositol triphosphate. RyR: Ryanodine receptor. STIM1: stroma interacting protein.