Calreticulin: Endoplasmic reticulum Ca²⁺ gatekeeper

Abstract

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.

Disrupted Endoplasmic Reticulum Ca2+ Handling: A Harβinger of β-Cell Failure

“…The roles of β-cell chaperone function have begun to emerge and have been well established in other cells. The C-terminal domain of calreticulin is responsible for buffering up to 50% of Ca 2+ ER , and thus, the overexpression of calreticulin increases Ca 2+ ER stores [ 121 , 122 , 123 ]. SOCE is also reduced in calreticulin overexpressing mouse L-fibroblasts due to increased Ca 2+ ER storage [ 124 ].…”