Coping with the calcium overload caused by cell injury: ER to the rescue.

Cells maintain their cytosolic calcium (Ca) in nanomolar range and use controlled increase in Ca for intracellular signaling. With the extracellular Ca in the millimolar range, there is a steep Ca gradient across the plasma membrane (PM). Thus, injury that damages PM, leads to a cytosolic Ca overload, which helps activate PM repair (PMR) response. However, in order to survive, the cells must cope with the Ca overload. In a recent study (Chandra J Cell Biol, doi: 10.1083/jcb.202006035) we have examined how cells cope with injury-induced cytosolic Ca overload. By monitoring Ca dynamics in the cytosol and endoplasmic reticulum (ER), we found that PM injury-triggered increase in cytosolic Ca is taken up by the ER. Pharmacological inhibition of ER Ca uptake interferes with this process and compromises the repair ability of the injured cells. Muscle cells from patients and mouse model for the muscular dystrophy showed that lack of Anoctamin 5 (ANO5)/Transmembrane protein 16E (TMEM16E), an ER-resident putative Ca-activated chloride channel (CaCC), are poor at coping with cytosolic Ca overload. Pharmacological inhibition of CaCC and lack of ANO5, both prevent Ca uptake into ER. These studies identify a requirement of Cl uptake by the ER in sequestering injury-triggered cytosolic Ca increase in the ER. Further, these studies show that ER helps injured cells cope with Ca overload during PMR, lack of which contributes to muscular dystrophy due to mutations in the ANO5 protein.