Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Distinct functions of nuclear and cytoplasmic calcium in the control of gene expression

Nature volume 385, pages 260–265 (1997)Cite this article

Abstract

Calcium entry into neuronal cells through voltage or ligand-gated ion channels triggers neuronal activity-dependent gene expression critical for adaptive changes in the nervous system1–5. Cytoplasmic calcium transients are often accompanied by an increase in the concentration of nuclear calcium6–9, but the functional significance of such spatially distinct calcium signals is unknown. Here we show that gene expression is differentially controlled by nuclear and cytoplasmic calcium signals which enable a single second messenger to generate diverse transcriptional responses. We used nuclear microinjection of a non-diffusible calcium chelator to block increases in nuclear, but not cytoplasmic, calcium concentrations following activation of L-type voltage-gated calcium channels. We showed that increases in nuclear calcium concentration control calcium-activated gene expression mediated by the cyclic-AMP-response element (CRE), and demonstrated that the CRE-binding protein CREB can function as a nuclear calcium-responsive transcription factor. A second signalling pathway, activating transcription through the serum-response element (SRE), is triggered by a rise in cytoplasmic calcium and does not require an increase in nuclear calcium.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

Buy

All prices are NET prices.

References

  1. Sheng, M. & Greenberg, M. E. Neuron 4, 477–485 (1990).

    CAS  Article  Google Scholar 

  2. Morgan, J. I. & Curran, T. Annu. Rev. Neurosci. 14, 421–451 (1991).

    CAS  Article  Google Scholar 

  3. Ghosh, A. & Greenberg, M. E. Science 268, 239–247 (1995).

    ADS  CAS  Article  Google Scholar 

  4. Berridge, M. J. Nature 361, 315–325 (1993).

    ADS  CAS  Article  Google Scholar 

  5. Clapham, D. E. Cell 80, 259–268 (1995).

    CAS  Article  Google Scholar 

  6. Segal, M. & Mannor, D. J. Physiol. 448, 655–676 (1992).

    CAS  Article  Google Scholar 

  7. Birch, B. D., Eng, D. L. & Kocsis, J. D. Proc. Natl Acad. Sci. USA 89, 7978–7982 (1992).

    ADS  CAS  Article  Google Scholar 

  8. Al-Mohanna, F. A., Caddy, K. W. T. & Bolsover, S. R. Nature 367, 745–750 (1994).

    ADS  CAS  Article  Google Scholar 

  9. O'Malley, D. M. J. Neurosci. 14, 5741–5758 (1994).

    CAS  Article  Google Scholar 

  10. Zheng, W., Rampe, D. & Triggle, D. J. Mol. Pharmacol. 40, 734–741 (1991).

    CAS  PubMed  Google Scholar 

  11. Bading, H., Ginty, D. D. & Greenberg, M. E. Science 260, 181–186 (1993).

    ADS  CAS  Article  Google Scholar 

  12. Sheng, M., Thompson, M. A. & Greenberg, M. E. Science 252, 1427–1430 (1991).

    ADS  CAS  Article  Google Scholar 

  13. Worley, P. F. et al. J. Neurosci. 13, 4776–4786 (1994).

    Article  Google Scholar 

  14. Bading, H. & Greenberg, M. E. Science 253, 912–914 (1991).

    ADS  CAS  Article  Google Scholar 

  15. Rosen, L. B., Ginty, D. D., Weber, M. J. & Greenberg, M. E. Neuron 12, 1207–1221 (1994).

    CAS  Article  Google Scholar 

  16. Rusanescu, G., Qi, H., Thomas, S. M., Brugge, J. S. & Halegoua, S. Neuron 15, 1415–1425 (1995).

    CAS  Article  Google Scholar 

  17. Jensen, K. F., Ohmstede, C.-A., Fisher, R. S. & Sahyoun, N. Proc. Natl Acad. Sci. USA 88, 2850–2853 (1991).

    ADS  CAS  Article  Google Scholar 

  18. Matthews, R. P. Mol. Cell. Biol. 14, 6107–6116 (1994).

    CAS  Article  Google Scholar 

  19. Sun, P., Enslen, H., Myung, P. S. & Maurer, R. A. Genes Dev. 8, 2527–2539 (1994).

    CAS  Article  Google Scholar 

  20. Miranti, C. K., Ginty, D. D., Huang, G., Chatila, T. & Greenberg, M. E. Mol. Cell. Biol. 15, 3672–3684 (1995).

    CAS  Article  Google Scholar 

  21. Ghosh, A., Carnahan, J. & Greenberg, M. E. Science 263, 1618–1623 (1994).

    ADS  CAS  Article  Google Scholar 

  22. Minta, A., Kao, J. P. Y. & Tsien, R. Y. J. Biol. Chem. 264, 8171–8178 (1989).

    CAS  PubMed  Google Scholar 

  23. Tsien, R. Y., Pozzan, T. & Rink, T. J. J. Cell Biol. 94, 325–334 (1982).

    CAS  Article  Google Scholar 

  24. Treisman, R. Cell 42, 889–902 (1985).

    CAS  Article  Google Scholar 

  25. Hill, C. S. & Treisman, R. EMBO J. 14, 5037–5047 (1995).

    CAS  Article  Google Scholar 

  26. Price, J., Turner, D. & Cepko, C. Proc. Natl Acad. Sci. USA 84, 156–160 (1987).

    ADS  CAS  Article  Google Scholar 

  27. Sheng, M., Dougan, S. T., McFadden, G. & Greenberg, M. E. Mol. Cell. Biol. 8, 2787–2796 (1988).

    CAS  Article  Google Scholar 

Download references

Author information

Affiliations

  1. MRC Laboratory of Molecular Biology, Hills Road, Cambridge, CB2 2QH, UK

    Giles E. Hardingham, Sangeeta Chawla, Claire M. Johnson & Hilmar Bading

Authors
  1. Giles E. Hardingham
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sangeeta Chawla
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Claire M. Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hilmar Bading
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Hardingham, G., Chawla, S., Johnson, C. et al. Distinct functions of nuclear and cytoplasmic calcium in the control of gene expression. Nature 385, 260–265 (1997). https://doi.org/10.1038/385260a0

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/385260a0

Further reading

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.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing