Skip to main content
PMC home page
Biophysical Journal logoLink to Biophysical Journal
. 2002 Feb;82(2):582–590. doi: 10.1016/S0006-3495(02)75423-4

A mathematical model predicts that calreticulin interacts with the endoplasmic reticulum Ca(2+)-ATPase.

Helen L Baker 1, Rachel J Errington 1, Sally C Davies 1, Anthony K Campbell 1
PMCID: PMC1301870  PMID: 11806903

Abstract

A robust mathematical model developed from single cell calcium (Ca(2+)) dynamics has enabled us to predict the consequences of over-expression of endoplasmic reticulum-located chaperones. Model predictions concluded that calreticulin interacts with the lumenal domain of the sarcoplasmic and endoplasmic reticulum Ca(2+)-activated ATPase (SERCA) pump, altering pump affinity for Ca(2+) (K(1/2) switches from 247 to 431 nM) and hence generating Ca(2+) oscillations. Expression of calreticulin in the ER generated an average of six transient-decline oscillations during the Ca(2+) recovery phase, upon exposure to maximal levels of the agonist ATP. In contrast, normal cells produced a single Ca(2+) transient with few or no oscillations. By conditioning the model to experimental data, parameters for generation and decay of IP(3) and SERCA pump kinetics were determined. To elucidate the possible source of the oscillatory behavior three possible oscillators, 1) IP(3), 2) IP(3)R, and 3) SERCA pump, were investigated and parameters constrained by experimental data to produce the best candidate. Each of the three oscillators generated very good fits with experimental data. However, converting a normal exponential recovery to a transient-decline oscillator predicted that the SERCA pump is the most likely candidate for calreticulin-mediated Ca(2+) release, highlighting the role of this chaperone as a signal protein within the endoplasmic reticulum.

Full Text

The Full Text of this article is available as a PDF (344.5 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Berridge M. J., Bootman M. D., Lipp P. Calcium--a life and death signal. Nature. 1998 Oct 15;395(6703):645–648. doi: 10.1038/27094. [DOI] [PubMed] [Google Scholar]
  2. Bezprozvanny I., Watras J., Ehrlich B. E. Bell-shaped calcium-response curves of Ins(1,4,5)P3- and calcium-gated channels from endoplasmic reticulum of cerebellum. Nature. 1991 Jun 27;351(6329):751–754. doi: 10.1038/351751a0. [DOI] [PubMed] [Google Scholar]
  3. Bootman M. D., Collins T. J., Peppiatt C. M., Prothero L. S., MacKenzie L., De Smet P., Travers M., Tovey S. C., Seo J. T., Berridge M. J. Calcium signalling--an overview. Semin Cell Dev Biol. 2001 Feb;12(1):3–10. doi: 10.1006/scdb.2000.0211. [DOI] [PubMed] [Google Scholar]
  4. Camacho P., Lechleiter J. D. Calreticulin inhibits repetitive intracellular Ca2+ waves. Cell. 1995 Sep 8;82(5):765–771. doi: 10.1016/0092-8674(95)90473-5. [DOI] [PubMed] [Google Scholar]
  5. Cuthbertson K. S., Chay T. R. Modelling receptor-controlled intracellular calcium oscillators. Cell Calcium. 1991 Feb-Mar;12(2-3):97–109. doi: 10.1016/0143-4160(91)90012-4. [DOI] [PubMed] [Google Scholar]
  6. De Young G. W., Keizer J. A single-pool inositol 1,4,5-trisphosphate-receptor-based model for agonist-stimulated oscillations in Ca2+ concentration. Proc Natl Acad Sci U S A. 1992 Oct 15;89(20):9895–9899. doi: 10.1073/pnas.89.20.9895. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Endy D., Brent R. Modelling cellular behaviour. Nature. 2001 Jan 18;409(6818):391–395. doi: 10.1038/35053181. [DOI] [PubMed] [Google Scholar]
  8. Fink C. C., Slepchenko B., Loew L. M. Determination of time-dependent inositol-1,4,5-trisphosphate concentrations during calcium release in a smooth muscle cell. Biophys J. 1999 Jul;77(1):617–628. doi: 10.1016/S0006-3495(99)76918-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Jeffery J., Kendall J. M., Campbell A. K. Apoaequorin monitors degradation of endoplasmic reticulum (ER) proteins initiated by loss of ER Ca(2+). Biochem Biophys Res Commun. 2000 Feb 24;268(3):711–715. doi: 10.1006/bbrc.2000.2194. [DOI] [PubMed] [Google Scholar]
  10. John L. M., Lechleiter J. D., Camacho P. Differential modulation of SERCA2 isoforms by calreticulin. J Cell Biol. 1998 Aug 24;142(4):963–973. doi: 10.1083/jcb.142.4.963. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Joseph S. K., Rice H. L., Williamson J. R. The effect of external calcium and pH on inositol trisphosphate-mediated calcium release from cerebellum microsomal fractions. Biochem J. 1989 Feb 15;258(1):261–265. doi: 10.1042/bj2580261. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Lièvremont J. P., Rizzuto R., Hendershot L., Meldolesi J. BiP, a major chaperone protein of the endoplasmic reticulum lumen, plays a direct and important role in the storage of the rapidly exchanging pool of Ca2+. J Biol Chem. 1997 Dec 5;272(49):30873–30879. doi: 10.1074/jbc.272.49.30873. [DOI] [PubMed] [Google Scholar]
  13. Llewelyn Roderick H., Llewellyn D. H., Campbell A. K., Kendall J. M. Role of calreticulin in regulating intracellular Ca2+ storage and capacitative Ca2+ entry in HeLa cells. Cell Calcium. 1998 Oct;24(4):253–262. doi: 10.1016/s0143-4160(98)90049-5. [DOI] [PubMed] [Google Scholar]
  14. Lytton J., Westlin M., Burk S. E., Shull G. E., MacLennan D. H. Functional comparisons between isoforms of the sarcoplasmic or endoplasmic reticulum family of calcium pumps. J Biol Chem. 1992 Jul 15;267(20):14483–14489. [PubMed] [Google Scholar]
  15. Meyer T., Stryer L. Calcium spiking. Annu Rev Biophys Biophys Chem. 1991;20:153–174. doi: 10.1146/annurev.bb.20.060191.001101. [DOI] [PubMed] [Google Scholar]
  16. Miyakawa T., Maeda A., Yamazawa T., Hirose K., Kurosaki T., Iino M. Encoding of Ca2+ signals by differential expression of IP3 receptor subtypes. EMBO J. 1999 Mar 1;18(5):1303–1308. doi: 10.1093/emboj/18.5.1303. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Putney J. W., Jr A model for receptor-regulated calcium entry. Cell Calcium. 1986 Feb;7(1):1–12. doi: 10.1016/0143-4160(86)90026-6. [DOI] [PubMed] [Google Scholar]
  18. Sneyd J., Keizer J., Sanderson M. J. Mechanisms of calcium oscillations and waves: a quantitative analysis. FASEB J. 1995 Nov;9(14):1463–1472. doi: 10.1096/fasebj.9.14.7589988. [DOI] [PubMed] [Google Scholar]
  19. Urano F., Bertolotti A., Ron D. IRE1 and efferent signaling from the endoplasmic reticulum. J Cell Sci. 2000 Nov;113(Pt 21):3697–3702. doi: 10.1242/jcs.113.21.3697. [DOI] [PubMed] [Google Scholar]
  20. Wagner J., Keizer J. Effects of rapid buffers on Ca2+ diffusion and Ca2+ oscillations. Biophys J. 1994 Jul;67(1):447–456. doi: 10.1016/S0006-3495(94)80500-4. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Biophysical Journal are provided here courtesy of The Biophysical Society

RESOURCES