Calreticulin is an upstream regulator of calcineurin

Ca(2+) is a signalling molecule involved in virtually every aspect of cell function. The endoplasmic reticulum (ER) is an important and dynamic organelle responsible for storage of the majority of intracellular Ca(2+). Within the ER lumen are proteins that function as Ca(2+) buffers and/or molecular chaperones including calreticulin, a multifunctional Ca(2+)-binding protein. Calreticulin-deficiency is lethal in utero due to impaired cardiac development. In the absence of calreticulin Ca(2+) storage capacity in the ER and InsP(3) receptor mediated Ca(2+) release from ER are compromised. Remarkably, over-expression of constitutively active calcineurin in the hearts of calreticulin deficient mice rescues them from embryonic lethality and produces live calreticulin deficient animals. These observations provide first evidence that calreticulin is a key upstream regulator of calcineurin in the Ca(2+)-signalling cascade and they highlight the importance of ER during early stages of cellular commitment and tissue development during organogenesis.