Figure 2.

Mechanisms of ER Ca²⁺ handling. (A) Stimulations of G-protein Coupled Receptors (GPCRs) and Receptor Tyrosine Kinases (RTKs) signal to phospholipase C-beta (PLC-beta) and PLC-gamma at the plasma membrane, respectively. This leads to PLC-mediated hydrolytic cleavage of phosphatidylinositol 4,5-bisphosphate, producing the Ca²⁺-mobilizing inositol-1,4,5-trisphosphate (IP₃) and diacylglycerol (DAG) (not shown in the figure) at the cell membrane. (B) Four molecules of IP₃ bind to the tetrameric IP₃ receptors (IP₃Rs) on the ER membrane, exposing their stimulatory Ca²⁺ binding sites while simultaneously obstructing inhibitory Ca²⁺ binding sites. Upon the co-binding of Ca²⁺ and IP₃, IP₃R channel pore opens, initiating ER Ca²⁺ release. (C) Elevated cytosolic Ca²⁺ further induces the opening of ryanodine receptors (RyRs) on the ER membrane, causing rapid and massive influx of ER Ca²⁺ into the cytosol. (D) Dwindling luminal ER Ca²⁺ results in the oligomerization of EF-SAM domain of stromal interaction molecules (STIMs), which, in turn, induces the multimerization of cytoplasmic STIM domains followed by translocation and assembly of STIM clusters at the ER-plasma membrane (ER-PM) junctions. In direct physical association with Orai channels on the plasma membrane, STIM clusters induce the opening of Orai channel pore, allowing extracellular Ca²⁺ entry into the cytosol. (E) Powered by ATP hydrolysis, the Sarco/Endoplasmic Reticulum Ca²⁺-ATPases (SERCAs) shuttle the influx of extracellular Ca²⁺ into the ER or SR, restoring cellular Ca²⁺ homeostasis. (F) ER Ca²⁺-leak channels, such as TMBIM6 and TMCO1, prevent ER Ca²⁺ over-filling.