Abstract
Although fluctuations in cytosolic Ca2+ concentration have a crucial role in relaying intracellular messages in the cell1, the dynamics of Ca2+ storage in and release from intracellular sequestering compartments remains poorly understood. The rapid release of stored Ca2+ requires large concentration gradients that had been thought to result from low-affinity buffering of Ca2+ by the polyanionic matrices within Ca2+-sequestering organelles2. However, our results here show that resting luminal free Ca2+ concentration inside the endoplasmic reticulum and in the mucin granules remains at low levels (20–35 μM). But after stimulation, the free luminal [Ca2+] increases, undergoing large oscillations, leading to corresponding oscillations of Ca2+ release to the cytosol. These remarkable dynamics of luminal [Ca2+] result from a fast and highly cooperative Ca2+/K+ ion-exchange process rather than from Ca2+ transport into the lumen. This common paradigm for Ca2+ storage and release, found in two different Ca2+-sequestering organelles, requires the functional interaction of three molecular components: a polyanionic matrix that functions as a Ca2+/K+ ion exchanger, and two Ca2+-sensitive channels, one to import K+ into the Ca2+-sequestering compartments, the other to release Ca2+ to the cytosol.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Berridge, M. J. The AM and FM of calcium signalling. Nature 386, 759–760 (1997).
Koch, G. L. E. The endoplasmic reticulum and calcium storage. BioEssays 12, 527–531 (1990).
Marszalek, P. E., Farrell, B., Verdugo, P. & Fernandez, J. M. Kinetics of release of serotonin from isolated secretory granules. II. Ion-exchange determines the diffusivity of serotonin. Biophys. J. 73, 1169–1183 (1997).
Verdugo, P. in Airway Secretion: Molecular Biophysics of Mucin Secretions (eds Takishima, T. & Shimura, S.) 101–117 (Marcel Dekker, New York, 1994).
Monck, J. R., Oberhauser, A. F., Keating, T. J. & Fernandez, J. M. Thin-section ratiometric Ca2+ images obtained by optical sectioning of Fura-2 loaded mast cells. J. Cell Biol. 116, 745–759 (1992).
Breckenridge, L. J. & Almers, W. Final steps in exocytosis observed in a cell with giant secretory granules. Proc. Natl Acad. Sci. USA 84, 1945–1949 (1987).
Terasaki, M., Song, J., Wong, J. R., Weiss, M. J. & Chen, L. B. Localization of endoplasmic reticulum in living and glutaraldehyde-fixed cells with fluorescent dyes. Cell 38, 101–108 (1984).
Belan, P. V. et al. Anew technique for assessing the microscopic distribution of cellular calcium exit sites. Pflugers Arch. 433, 200–208 (1996).
Tse, T. W., Tse, A. & Hille, B. Cyclic Ca2+ changes in intracellular stores of gonadotropes during gonadotropin-releasing hormone-stimulated Ca2+ oscillations. Proc. Natl Acad. Sci. USA 91, 9750–9754 (1994).
Lytton, J., Westlin, M. & Hanley, M. R. Thapsigargin inhibits the sarcoplasmic or endoplasmic reticulum Ca-ATPase family of calcium pumps. J. Biol. Chem. 266, 17067–17071 (1991).
Hehl, S., Golard, A. & Hille, B. Involvement of mitochondria in intracellular calcium sequestration by rat gonadotropes. Cell Calcium 20, 515–524 (1996).
Ghosh, T. K., Eis, P. S., Mullaney, J. M., Ebert, C. L. & Gill, D. L. Competitive, reversible, and potent antagonism of inositol 1,4,5-trisphosphate-activated calcium release by heparin. J. Biol. Chem. 263, 11075–11079 (1988).
Latorre, R., Oberhauser, A., Labarca, P. & Alvarez, O. Varieties of calcium-activated potassium channels. Annu. Rev. Physiol. 51, 385–399 (1989).
Sasaki, S., Nakagaki, I., Kondo, H. & Hori, S. Changes in element concentrations induced by agonist in pig pancreatic acinar cells. Pflugers Arch. 432, 538–545 (1996).
O'Rourke, F. et al. Ca2+ release by inositol (1,4,5)-trisphosphate is blocked by the K+-channel blockers apamin and tetraphenylammonium ion, and a monoclonal antibody to a 63 kDa membrane protein: reversal of blockade by K+ ionophores nigericin and valinomycin and purification of the 63 kDa antibody-binding protein. Biochem. J. 300, 673–683 (1994).
Joseph, S. K. & Williamson, J. R. Characteristics of inositol trisphosphate-mediated Ca2+ release from permeabilized hepatocytes. J. Biol. Chem. 261, 14658–14664 (1986).
Meldolesi, J. & Pozzan, T. The endoplasmic reticulum Ca2+ store: a view from the lumen. Trends Biol. Sci. 23, 10–14 (1998).
Ikemoto, N., Antonui, B., Kang, J. J., Meszaros, L. G. & Rojat, M. Intravesicular calcium trasient during calcium release from sarcoplasmic reticulum. Biochemistry 30, 5230–5237 (1991).
Mitchell, R. D., Simmerman, H. K. B. & Jones, L. R. Ca2+ binding effects on protein conformation and protein interactions of canine cardiac calsequestrin. J. Biol. Chem. 263, 1376–1381 (1988).
Forstner, J. F. & Forstner, G. G. Calcium binding to intestinal goblet mucin. Biochim. Biophys. Acta 386, 283–292 (1975).
van de Put, F. H. M. M. & Elliott, A. C. The endoplasmic reticulum can act as a functional Ca2+ store in all subcellular regions of the pancreatic acinar cell. J. Biol. Chem. 272, 27764–27770 (1997).
Blondel, O., Bell, G. I. & Seino, S. Inositol 1,4,5-trisphosphate receptors, secretory granules and secretion in endocrine and neuroendrocrine cells. Trends Neurosci. 18, 157–161 (1995).
Gerasimenko, O. V., Gerasimenko, J. V., Belan, P. V. & Petersen, O. H. Inositol trisphosphate and cyclic ADP-ribose-mediated release of Ca2+ from single isolated pancreatic zymogen granules. Cell 84, 473–480 (1996).
Yule, D. I., Ernst, S. A., Ohnishi, H. & Wojcikiewicz, R. J. H. Evidence that zymogen granules are not a physiologically relevant calcium pool. J. Biol. Chem. 272, 9093–9098 (1997).
Lorez, H. P. & Da Prada, M. Fluorescence microscopical study of 5-hydroxytryptamine storage organelles in mepacrine-incubated blood plateletes of beige mice (Chediak–Higashi syndrome). Experientia 34, 663–664 (1978).
Verdugo, P. Ca2+-dependent hormonal stimulation of ciliary activity. Nature 283, 764–765 (1980).
Davis, C. W. in Airway Mucus: Basic Mechanisms and Clinical Perspectives (eds Rogers, D. F. & Lethem, M. I.) 149–177 (Springer-Verlag, Basel, 1997).
Finch, E. A., Turner, T. J. & Goldin, S. M. Calcium as a coagonist of inositol 1,4,5-trisphosphate-induced calcium release. Science 252, 443–446 (1991).
Aitken, M. L., Villalon, M., Pier, M., Verdugo, P. & Nameroff, M. Characterization of a marker tracheal basal cells. Exp. Lung Res. 21, 1–16 (1995).
Kao, J. P. Y. in A Practical Guide to the Study of Calcium in Living Cells (ed. Nuccitelli, R.) 155–181 (Academic, San Diego, (1994)).
Acknowledgements
We thank M. Pier for assistance in cell culture, and P. Detwiler, J. M. Fernandez, R.Hart, B. Hille, T. Hinds, A. Gordon, G. Pollack and J. L. Vergara for suggestions and the critical review of the manuscript. This work was funded by grants from USA NSF, the USA DOE and the CONRAD Program of Mellon Foundation. W.-C.C. and T.N. were supported by scholarships from the Center for Nanotechnology and the MSTP Program from the University of Washington, respectively.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Nguyen, T., Chin, WC. & Verdugo, P. Role of Ca2+/K+ ion exchange in intracellular storage and release of Ca2+. Nature 395, 908–912 (1998). https://doi.org/10.1038/27686
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/27686
This article is cited by
-
A New Endoplasmic Reticulum (ER)-Targeting Fluorescent Probe for the Imaging of Cysteine in Living Cells
Journal of Fluorescence (2020)
-
Perovskite Nanoparticles Toxicity Study on Airway Epithelial Cells
Nanoscale Research Letters (2019)
-
Effect of ionic strength and seawater cations on hagfish slime formation
Scientific Reports (2018)
-
A mixture of anatase and rutile TiO2 nanoparticles induces histamine secretion in mast cells
Particle and Fibre Toxicology (2012)
-
Time-resolved release of calcium from an epithelial cell monolayer during mucin secretion
European Biophysics Journal (2011)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.