Inositol 1,4,5-trisphosphate (IP3)-mediated calcium (Ca2+) signaling i
s subject to cytosolic and luminal regulatory mechanisms. In Xenopus o
ocytes, Ca2+-sensitive gating of the IP3 receptor (IP(3)R) produces re
petitive waves of Ca2+ release. We examined the role of the luminal Ca
2+-binding protein calreticulin (CRT) in IP3-mediated Ca2+ signaling b
y using Ca2+ wave activity as a sensitive Ca2+ release assay. Overexpr
ession of CRT inhibited repetitive IP3-induced Ca2+ waves. Deletion mu
tagenesis demonstrated that CRT inhibition was mediated by the high af
finity-low capacity Ca2+-binding domain, which contributes little to C
a2+ storage. This novel function of CRT in intracellular Ca2+ signalin
g may be regulated by Ca2+ occupancy of the high affinity binding site
.