Figure 1.

A graphical representation of calcium homeostasis attainment. A ER-Cytosol-Plasma membrane communications. ER-resident calcium pump proteins SERCAs are responsible for transporting Ca²⁺ from the cytosolic into the ER. IP3Rs, or RyRs mediate the release of calcium from the ER in response to the increased IP3 following hormone or growth factor stimulation, or increased cytosolic Ca²⁺ levels. When ER Ca²⁺ concentration is reduced, STIM can be activated to interact with and activate plasma membrane-localized Ca²⁺ channel ORAI1, leading to extracellular Ca²⁺ being influx and the subsequent SERCA-mediated ER Ca²⁺ refilling. Nevertheless, during ER Ca²⁺ overload, the TMCO1 can be stimulated to release Ca²⁺ into the cytosol by forming a selective Ca²⁺ channel through monomer-to-tetramer transformation, a process termed SOICR. B ER-Mitochondria communications. The ER and mitochondria are interconnected both structurally and functionally through a specialized microdomain known as the MAM. Within MAMs, several proteins such as Grp-75, VDAC1, and IP3R play a crucial role in regulating Ca²⁺ release from the ER and an efficient mitochondrial Ca²⁺ uptake. C ER–lysosome communications. Lysosomal Ca²⁺ depletion initiates the IP3R-mediated Ca²⁺ release from ER and subsequent lysosome Ca²⁺ refilling through the Ca²⁺ transporter or Ca²⁺/H⁺ exchanger (CAX). Furthermore, ER can restore Ca²⁺ from the lysosomes through the stimulation of two distinct mechanisms: the activation of TPC by NAADP, or the activation of TRPML1