Calreticulin modulates capacitative Ca2+ influx by controlling the extent of inositol 1,4,5-trisphosphate-induced Ca2+ store depletion.
Calreticulin (CRT) is a highly conserved Ca(2+)-binding protein that resides in the lumen of the endoplasmic reticulum (ER). We overexpressed CRT in Xenopus oocytes to determine how it could modulate inositol 1,4,5-trisphosphate (InsP(3))-induced Ca(2+) influx. Under conditions where it did not affect the spatially complex elevations in free cytosolic Ca(2+) concentration ([Ca(2+)](i)) due to InsP(3)-induced Ca(2+) release, overexpressed CRT decreased by 46% the Ca(2+)-gated Cl(-) current due to Ca(2+) influx. Deletion mutants revealed that CRT requires its high capacity Ca(2+)-binding domain to reduce the elevations of [Ca(2+)](i) due to Ca(2+) influx. This functional domain was also required for CRT to attenuate the InsP(3)-induced decline in the free Ca(2+) concentration within the ER lumen ([Ca(2+)](ER)), as monitored with a "chameleon" indicator. Our data suggest that by buffering [Ca(2+)](ER) near resting levels, CRT may prevent InsP(3) from depleting the intracellular stores sufficiently to activate Ca(2+) influx.
Xu
W
W
Veterans Affairs Medical Center and Departments of Medicine and Physiology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
Longo
F J
FJ
Wintermantel
M R
MR
Jiang
X
X
Clark
R A
RA
DeLisle
S
S
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D037282:Calreticulin; D004721:Endoplasmic Reticulum / Q000378:metabolism; D018922:HL-60 Cells; D006706:Homeostasis; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism*; D008954:Models, Biological; D009865:Oocytes / Q000378:metabolism; D012261:Ribonucleoproteins / Q000378:metabolism*; D014981:Xenopus
D002135:Calcium-Binding Proteins; D037282:Calreticulin; D012261:Ribonucleoproteins; D015544:Inositol 1,4,5-Trisphosphate; D002118:Calcium