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 (IP(3)R) 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.