Calreticulin inhibits repetitive intracellular Ca²⁺ waves

Inositol 1,4,5-trisphosphate (IP₃)-mediated calcium (Ca²⁺) signaling is subject to cytosolic and luminal regulatory mechanisms. In Xenopus oocytes, Ca²⁺-sensitive gating of the IP₃ receptor (IP₃R) produces repetitive waves of Ca²⁺ release. We examined the role of the luminal Ca²⁺-binding protein calreticulin (CRT) in IP₃-mediated Ca²⁺ signaling by using Ca²⁺ wave activity as a sensitive Ca²⁺ release assay. Overexpression of CRT inhibited repetitive IP₃-induced Ca²⁺ waves. Deletion mutagenesis demonstrated that CRT inhibition was mediated by the high affinity-low capacity Ca²⁺-binding domain, which contributes little to Ca²⁺ storage. This novel function of CRT in intracellular Ca²⁺ signaling may be regulated by Ca²⁺ occupancy of the high affinity binding site.