Calreticulin: Endoplasmic reticulum Ca 2+ gatekeeper

Abstract Endoplasmic reticulum (ER) luminal Ca 2+ is vital for the function of the ER and regulates many cellular processes. Calreticulin is a highly conserved, ER‐resident Ca 2+ binding protein and lectin‐like chaperone. Over four decades of studying calreticulin demonstrate that this protein plays a crucial role in maintaining Ca 2+ supply under different physiological conditions, in managing access to Ca 2+ and how Ca 2+ is used depending on the environmental events and in making sure that Ca 2+ is not misused. Calreticulin plays a role of ER luminal Ca 2+ sensor to manage Ca 2+ ‐dependent ER luminal events including maintaining interaction with its partners, Ca 2+ handling molecules, substrates and stress sensors. The protein is strategically positioned in the lumen of the ER from where the protein manages access to and distribution of Ca 2+ for many cellular Ca 2+ ‐signalling events. The importance of calreticulin Ca 2+ pool extends beyond the ER and includes influence of cellular processes involved in many aspects of cellular pathophysiology. Abnormal handling of the ER Ca 2+ contributes to many pathologies from heart failure to neurodegeneration and metabolic diseases.