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

Abstract

Cells maintain their cytosolic calcium (Ca²⁺) in nanomolar range and use controlled increase in Ca²⁺ for intracellular signaling. With the extracellular Ca²⁺ in the millimolar range, there is a steep Ca²⁺ gradient across the plasma membrane (PM). Thus, injury that damages PM, leads to a cytosolic Ca²⁺ overload, which helps activate PM repair (PMR) response. However, in order to survive, the cells must cope with the Ca²⁺ overload. In a recent study (Chandra et al. J Cell Biol, doi: 10.1083/jcb.202006035) we have examined how cells cope with injury-induced cytosolic Ca²⁺ overload. By monitoring Ca²⁺ dynamics in the cytosol and endoplasmic reticulum (ER), we found that PM injury-triggered increase in cytosolic Ca²⁺ is taken up by the ER. Pharmacological inhibition of ER Ca²⁺ 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 Ca²⁺-activated chloride channel (CaCC), are poor at coping with cytosolic Ca²⁺ overload. Pharmacological inhibition of CaCC and lack of ANO5, both prevent Ca²⁺ uptake into ER. These studies identify a requirement of Cl^- uptake by the ER in sequestering injury-triggered cytosolic Ca²⁺ increase in the ER. Further, these studies show that ER helps injured cells cope with Ca²⁺ overload during PMR, lack of which contributes to muscular dystrophy due to mutations in the ANO5 protein.