FIGURE 1: ER-mediated buffering of injury-triggered cytosolic Ca²⁺ increase. Plasma membrane acts as a barrier to maintain cytosolic ion balance, which is disrupted by cell injury leading to influx of ions such as Ca²⁺ (1). This increase in cytosolic Ca²⁺ activates opening of the ER-resident ion channel ANO5 and increases influx of the Cl^– ions into the ER lumen (2). This Cl^– ion serves as the counterion to maintain ER electroneutrality as the excess cytosolic Ca²⁺ is pumped into the ER lumen by the ER-resident Ca²⁺ pump SERCA (3). Together, these transporters enable buffering the cytosolic Ca²⁺ overload caused by PM injury, and their inhibition prevents clearance of cytosolic Ca²⁺ increase in the injured cell, compromising repair of the injured cell.