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A correction to this article has been published: J. Cell Biol. 155 (6) 1083
Published online 27 August 2001. doi:10.1083/jcb.200102073
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© The Rockefeller University Press, 0021-9525/2001/9/961 $5.00
The Journal of Cell Biology, Volume 154, Number 5, September 3, 2001 961-972

Article

Functional specialization of calreticulin domains



Kimitoshi Nakamura1, Anna Zuppini1, Serge Arnaudeau2, Jeffery Lynch1, Irfan Ahsan1, Ryoko Krause3, Sylvia Papp4, Humbert De Smedt5, Jan B. Parys5, Werner Müller-Esterl6, Daniel P. Lew3, Karl-Heinz Krause7, Nicolas Demaurex2, Michal Opas4 and Marek Michalak1

1 Canadian Institutes of Health Research Group in Molecular Biology of Membranes and the Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2H7, Canada
2 Department of Physiology, University of Geneva Medical Center, CH-1211 Geneva, Switzerland
3 Division of Infectious Diseases, Geneva University Hospital, CH-1211 Geneva, Switzerland
4 Department of Anatomy and Cell Biology, University of Toronto, Toronto, Ontario, Canada M5S 1A1
5 Laboratorium of Physiology, Katholieke Universiteit Leuven, 3000 Leuven, Belgium
6 Institute for Biochemistry, University Hospital Frankfurt, D-60590 Frankfurt, Germany
7 Department of Geriatrics, Geneva University Hospital, CH-1225 Geneva, Switzerland

Address correspondence to Marek Michalak, Dept. of Biochemistry, University of Alberta, Edmonton, Alberta, Canada T6G 2H7. Tel.: (780) 492-2256. Fax: (780) 492-0886. E-mail: marek.michalak{at}ualberta.ca

Calreticulin is a Ca2+-binding chaperone in the endoplasmic reticulum (ER), and calreticulin gene knockout is embryonic lethal. Here, we used calreticulin-deficient mouse embryonic fibroblasts to examine the function of calreticulin as a regulator of Ca2+ homeostasis. In cells without calreticulin, the ER has a lower capacity for Ca2+ storage, although the free ER luminal Ca2+ concentration is unchanged. Calreticulin-deficient cells show inhibited Ca2+ release in response to bradykinin, yet they release Ca2+ upon direct activation with the inositol 1,4,5-trisphosphate (InsP3). These cells fail to produce a measurable level of InsP3 upon stimulation with bradykinin, likely because the binding of bradykinin to its cell surface receptor is impaired. Bradykinin binding and bradykinin-induced Ca2+ release are both restored by expression of full-length calreticulin and the N + P domain of the protein. Expression of the P + C domain of calreticulin does not affect bradykinin-induced Ca2+ release but restores the ER Ca2+ storage capacity. Our results indicate that calreticulin may play a role in folding of the bradykinin receptor, which affects its ability to initiate InsP3-dependent Ca2+ release in calreticulin-deficient cells. We concluded that the C domain of calreticulin plays a role in Ca2+ storage and that the N domain may participate in its chaperone functions.

Key Words: calreticulin-deficient cells; calcium homeostasis; chaperone; bradykinin receptor; endoplasmic reticulum


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