Calreticulin: Endoplasmic reticulum Ca²⁺ gatekeeper

Endoplasmic reticulum (ER) luminal Ca²⁺ is vital for the function of the ER and regulates many cellular processes. Calreticulin is a highly conserved, ER-resident Ca²⁺ binding protein and lectin-like chaperone. Over four decades of studying calreticulin demonstrate that this protein plays a crucial role in maintaining Ca²⁺ supply under different physiological conditions, in managing access to Ca²⁺ and how Ca²⁺ is used depending on the environmental events and in making sure that Ca²⁺ is not misused. Calreticulin plays a role of ER luminal Ca²⁺ sensor to manage Ca²⁺-dependent ER luminal events including maintaining interaction with its partners, Ca²⁺ 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 Ca²⁺ for many cellular Ca²⁺-signalling events. The importance of calreticulin Ca²⁺ pool extends beyond the ER and includes influence of cellular processes involved in many aspects of cellular pathophysiology. Abnormal handling of the ER Ca²⁺ contributes to many pathologies from heart failure to neurodegeneration and metabolic diseases.