Calreticulin Modulates Capacitative Ca2+ Influx by Controlling the Extent of Inositol 1,4,5-Trisphosphate-induced Ca2+ Store Depletion

Abstract Calreticulin (CRT) is a highly conserved Ca2+-binding protein that resides in the lumen of the endoplasmic reticulum (ER). We overexpressed CRT in Xenopusoocytes to determine how it could modulate inositol 1,4,5-trisphosphate (InsP3)-induced Ca2+ influx. Under conditions where it did not affect the spatially complex elevations in free cytosolic Ca2+ concentration ([Ca2+]i) due to InsP3-induced Ca2+ release, overexpressed CRT decreased by 46% the Ca2+-gated Cl− current due to Ca2+influx. Deletion mutants revealed that CRT requires its high capacity Ca2+-binding domain to reduce the elevations of [Ca2+]i due to Ca2+ influx. This functional domain was also required for CRT to attenuate the InsP3-induced decline in the free Ca2+concentration within the ER lumen ([Ca2+]ER), as monitored with a “chameleon” indicator. Our data suggest that by buffering [Ca2+]ER near resting levels, CRT may prevent InsP3 from depleting the intracellular stores sufficiently to activate Ca2+ influx.