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.

  • Article
  • Published:

Nuclear calcium signaling controls CREB-mediated gene expression triggered by synaptic activity

Nature Neuroscience volume 4, pages 261–267 (2001)Cite this article

Abstract

Information storage in the nervous system requires transcription triggered by synaptically evoked calcium signals. It has been suggested that translocation of calmodulin into the nucleus, initiated by submembranous calcium transients, relays synaptic signals to CREB. Here we show that in hippocampal neurons, signaling to CREB can be activated by nuclear calcium alone and does not require import of cytoplasmic proteins into the nucleus. The nucleus is particularly suited to integrate neuronal firing patterns, and specifies the transcriptional outputs through a burst frequency-to-nuclear calcium amplitude conversion. Calcium release from intracellular stores promotes calcium wave propagation into the nucleus, which is critical for CREB-mediated transcription by synaptic NMDA receptors. Pharmacological or genetic modulation of nuclear calcium may directly affect transcription-dependent memory and cognitive functions.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Dynamics of calmodulin localization in hippocampal neurons: uncoupling of synaptic activity-induced CREB phosphorylation from import of proteins into the nucleus.
Figure 2: The nuclear calcium pool specifies the transcriptional response.
Figure 3: NMDA receptor-induced calcium release from intracellular stores promotes calcium wave propagation to the nucleus, which is critical for CREB-mediated transcription by synaptic activity.
Figure 4: The nuclear calcium pool is sufficient to signal to CREB.

Similar content being viewed by others

References

  1. Milner, B., Squire, L. R. & Kandel, E. R. Cognitive neuroscience and the study of memory. Neuron 20, 445–468 (1998).

    Article  CAS  Google Scholar 

  2. Ghosh, A. & Greenberg, M. E. Calcium signaling in neurons: molecular mechanisms and cellular consequences. Science 268, 239–247 (1995).

    Article  CAS  Google Scholar 

  3. Hardingham, G. E. & Bading, H. Calcium as a versatile second messenger in the control of gene expression. Microsc. Res. Tech. 46, 348–355 (1999).

    Article  CAS  Google Scholar 

  4. Bailey, C. H., Bartsch, D. & Kandel, E. R. Toward a molecular definition of long-term memory storage. Proc. Natl. Acad. Sci. USA 93, 13445–13452 (1996).

    Article  CAS  Google Scholar 

  5. Silva, A. J., Kogan, J. H., Frankland, P. W. & Kida, S. CREB and memory. Annu. Rev. Neurosci. 21, 127–148 (1998).

    Article  CAS  Google Scholar 

  6. Ahn, S., Riccio, A. & Ginty, D. D. Spatial considerations for stimulus-dependent transcription in neurons. Annu. Rev. Physiol. 62, 803–823 (2000).

    Article  CAS  Google Scholar 

  7. Adams, J. P., Roberson, E. D., English, J. D., Selcher, J. C. & Sweatt, J. D. MAPK regulation of gene expression in the central nervous system. Acta. Neurobiol. Exp. (Warsz.) 60, 377–394 (2000).

    CAS  Google Scholar 

  8. Bading, H. Transcription-dependent neuronal plasticity: The nuclear calcium hypothesis. Eur. J. Biochem. 267, 5280–5283 (2000).

    Article  CAS  Google Scholar 

  9. Bading, H. & Greenberg, M. E. Stimulation of protein tyrosine phosphorylation by NMDA receptor activation. Science 253, 912–914 (1991).

    Article  CAS  Google Scholar 

  10. Ginty, D. D., Bonni, A. & Greenberg, M. E. Nerve growth factor activates a Ras-dependent protein kinase that stimulates c-fos transcription via phosphorylation of CREB. Cell 77, 713–725 (1994).

    Article  Google Scholar 

  11. Xing, J., Ginty, D. D. & Greenberg, M. E. Coupling of the RAS-MAPK pathway to gene activation by RSK2, a growth factor-regulated CREB kinase. Science 273, 959–963 (1996).

    Article  CAS  Google Scholar 

  12. Impey, S. et al. Cross talk between ERK and PKA is required for Ca2+ stimulation of CREB-dependent transcription and ERK nuclear translocation. Neuron 21, 869–883 (1998).

    Article  CAS  Google Scholar 

  13. Chawla, S., Hardingham, G. E., Quinn, D. R. & Bading, H. CBP: a signal-regulated transcriptional coactivator controlled by nuclear calcium and CaM kinase IV. Science 281, 1505–1509 (1998).

    Article  CAS  Google Scholar 

  14. Sheng, M., Thompson, M. A. & Greenberg, M. E. CREB: a Ca2+-regulated transcription factor phosphorylated by calmodulin-dependent kinases. Science 252, 1427–1430 (1991).

    Article  CAS  Google Scholar 

  15. Cruzalegui, F. H. & Means, A. R. Biochemical characterization of the multifunctional calcium/calmodulin dependent protein kinase type IV expressed in insect cells. J. Biol. Chem. 268, 26171–26178 (1993).

    CAS  PubMed  Google Scholar 

  16. Sun, P., Enslen, H., Myung, P. S. & Maurer, R. A. Differential activation of CREB by Ca2+/calmodulin-dependent protein kinases type II and type IV involves phosphorylation of a site that negatively regulates activity. Genes Dev. 8, 2527–2539 (1994).

    Article  CAS  Google Scholar 

  17. Matthews, R. P. et al. Calcium/calmodulin-dependent protein kinase types II and IV differentially regulate CREB-dependent gene expression. Mol. Cell. Biol. 14, 6107–6116 (1994).

    Article  CAS  Google Scholar 

  18. Bito, H., Deisseroth, K. & Tsien, R. W. CREB phosphorylation and dephosphorylation: a Ca2+ and stimulus duration-dependent switch for hippocampal gene expression. Cell 87, 1203–1214 (1996).

    Article  CAS  Google Scholar 

  19. Hardingham, G. E., Chawla, S., Cruzalegui, F. H. & Bading, H. Control of recruitment and transcription-activating function of CBP determines gene regulation by NMDA receptors and L-type calcium channels. Neuron 22, 789–798 (1999).

    Article  CAS  Google Scholar 

  20. Sheng, M., Dougan, S. T., McFadden, G. & Greenberg, M. E. Calcium and growth factor pathways of c-fos transcriptional activation require distinct upstream regulatory sequences. Mol. Cell. Biol. 8, 2787–2796 (1988).

    Article  CAS  Google Scholar 

  21. Bonni, A., Ginty, D. D., Dudek, H. & Greenberg, M. E. Serine 133-phosphorylated CREB induces transcription via a cooperative mechanism that may confer specificity to neurotrophin signals. Mol. Cell. Neurosci. 6, 168–183 (1995).

    Article  CAS  Google Scholar 

  22. Hu, S.-C., Chrivia, J. & Ghosh, A. Regulation of CBP-mediated transcription by neuronal calcium signaling. Neuron 22, 799–808 (1999).

    Article  CAS  Google Scholar 

  23. Goodman, R. H. & Smolik, S. CBP/p300 in cell growth, transformation, and development. Genes Dev. 14, 1553–1577 (2000).

    CAS  PubMed  Google Scholar 

  24. Cruzalegui, F. H., Hardingham, G. E. & Bading, H. c-Jun functions as a calcium-regulated transcriptional activator in the absence of JNK/SAPK1 activation. EMBO J. 18, 1335–1344 (1999).

    Article  CAS  Google Scholar 

  25. Deisseroth, K., Heist, E. K. & Tsien, R. W. Calmodulin translocation to the nucleus supports CREB phosphorylation in hippocampal neurons. Nature 392, 198–202 (1998).

    Article  CAS  Google Scholar 

  26. Pruschy, M., Ju, Y., Spitz, L., Carafoli, E. & Goldfarb, D. S. Facilitated nuclear transport of calmodulin in tissue culture cells. J. Cell Biol. 127, 1527–1536 (1994).

    Article  CAS  Google Scholar 

  27. Lerea, L. S., Butler, L. S. & McNamara, J. O. NMDA and non–NMDA receptor-mediated increase of c-fos mRNA in dentate gyrus neurons involved calcium influx via different routes. J. Neurosci. 12, 2973–2981 (1992).

    Article  CAS  Google Scholar 

  28. Bading, H., Ginty, D. D. & Greenberg, M. E. Regulation of gene expression in hippocampal neurons by distinct calcium signaling pathways. Science 260, 181–186 (1993).

    Article  CAS  Google Scholar 

  29. Hardingham, G. E., Chawla, S., Johnson, C. M. & Bading, H. Distinct functions of nuclear and cytoplasmic calcium in the control of gene expression. Nature 385, 260–265 (1997).

    Article  CAS  Google Scholar 

  30. Fields, R. D., Esthete, F., Stevens, B., & Itoh, K. Action potential-dependent regulation of gene expression: temporal specificity in calcium, cAMP-reponsive element binding proteins, and mitogen-activated protein kinase signalling. J. Neurosci. 17, 7252–7266 (1997).

    Article  CAS  Google Scholar 

  31. Ginty, D. D. et al. Regulation of CREB phosphorylation in the suprachiasmatic nucleus by light and a circadian clock. Science 268, 238–241 (1993).

    Article  Google Scholar 

  32. Hagiwara, M. et al. Transcriptional attenuation following cAMP induction requires PP-1-mediated dephosphorylation of CREB. Cell 70, 105–113 (1992).

    Article  CAS  Google Scholar 

  33. Lipp, P., Thomas, D., Berridge, M. J. & Bootman, M. D. Nuclear calcium signalling by individual cytoplasmic calcium puffs. EMBO J. 16, 7166–7173 (1997).

    Article  CAS  Google Scholar 

  34. Nakazawa, H. & Murphy, T. H. Activation of nuclear calcium dynamics by synaptic stimulation in cultured cortical neurons. J. Neurochem. 73, 1075–1083 (1999).

    Article  CAS  Google Scholar 

  35. Olwin, B. B., Edelman, A. M., Krebs, E. G. & Storm, D. R. Quantitation of energy coupling between Ca2+, calmodulin, skeletal muscle myosin light chain kinase, and kinase substrates. J. Biol. Chem. 259, 10949–10955 (1984).

    CAS  PubMed  Google Scholar 

  36. Shaw, P., Schröter, H. & Nordheim, A. The ability of a ternary complex to form over the serum response element correlates with serum inducibility of the c-fos promoter. Cell 56, 563–572 (1989).

    Article  CAS  Google Scholar 

  37. Treisman, R. Ternary complex factors: growth factor regulated transcriptional activators. Curr. Opin. Genet. Dev. 4, 96–101 (1994).

    Article  CAS  Google Scholar 

  38. Johnson, C. M., Hill, C. S., Chawla, S., Treisman, R. & Bading, H. Calcium controls gene expression via three distinct pathways that can function independently of the Ras/Mitogen-activated protein kinases (ERKs) signaling cascade. J. Neurosci. 17, 6189–6202 (1997).

    Article  CAS  Google Scholar 

  39. Magee, J. C. & Johnston, D. A synaptically controlled, associative signal for Hebbian plasticity in hippocampal neurons. Science 275, 209–213 (1997).

    Article  CAS  Google Scholar 

  40. Markram, H., Lübke, J., Frotscher, M. & Sakmann, B. Regulation of synaptic efficacy by coincidence of postsynaptic APs and EPSPs. Science 275, 213–215 (1997).

    Article  CAS  Google Scholar 

  41. Larkum, M. E., Zhu, J. J. & Sakmann, B. A new cellular mechanism for coupling inputs arriving at different cortical layers. Nature 398, 338–341 (1999).

    Article  CAS  Google Scholar 

  42. Nakamura, T., Barbara, J. G., Nakamura, K. & Ross, W. N. Synergistic release of Ca2+ from IP3-sensitive stores evoked by synaptic activation of mGluRs paired with backpropagating action potentials. Neuron 24, 727–737 (1999).

    Article  CAS  Google Scholar 

  43. Christie, B. R., Eliot, L. S., Ito, K., Miyakawa, H. & Johnston, D. Different Ca2+ channels in soma and dendrites of hippocampal pyramidal neurons mediate spike-induced Ca2+ influx. J. Neurophysiol. 73, 2553–2557 (1995).

    Article  CAS  Google Scholar 

  44. Schiller, J., Helmchen, F. & Sakmann B. Spatial profile of dendritic calcium transients evoked by action potentials in rat neocortical pyramidal neurones. J. Physiol. (Lond.) 487, 583–600 (1995).

    Article  CAS  Google Scholar 

  45. Frey, U. & Morris, R. G. Synaptic tagging and long-term potentiation. Nature 385, 533–536 (1997).

    Article  CAS  Google Scholar 

  46. Dolmetsch, R. E., Lewis, R. S., Goodnow, C. C. & Healy, J. I. Differential activation of transcription factors induced by calcium response amplitude and duration. Nature 386, 855–858 (1997).

    Article  CAS  Google Scholar 

  47. Deyo, R. A., Straube, K. T. & Disterhoft, J. F. Nimodipine facilitates associative learning in aging rabbits. Science 243, 809–811 (1989).

    Article  CAS  Google Scholar 

  48. Levere, T. E. & Walker, A. Old age and cognition: enhancement of recent memory in aged rats by the calcium channel blocker nimodipine. Neurobiol. Aging 13, 63–66 (1991).

    Article  Google Scholar 

  49. Sandin, M., Jasmin, S. & Levere, T. E. Aging and cognition: facilitation of recent memory in aged nonhuman primates by nimodipine. Neurobiol. Aging 11, 573–575 (1990).

    Article  CAS  Google Scholar 

  50. Morich, F. J. et al. Nimodipine in the treatment of probable Alzheimer's disease—results of two multicentre trials. Clin. Drug Invest. 11, 185–195 (1996).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank N.R. Hardingham and J. Jack for discussion and background electrophysiological data, E. Gruenstein for advice on the 4-AP experiments, and B. Wisden for discussion. This work was supported by the MRC, Dunhill Medical Trust, The Royal College of Surgeons of England, the Sackler Medical Research Centre and Clare College, Cambridge.

Author information

Authors and Affiliations

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

    Giles E. Hardingham, Fiona J. L. Arnold & Hilmar Bading

Authors
  1. Giles E. Hardingham
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fiona J. L. Arnold
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hilmar Bading
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hilmar Bading.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hardingham, G., Arnold, F. & Bading, H. Nuclear calcium signaling controls CREB-mediated gene expression triggered by synaptic activity. Nat Neurosci 4, 261–267 (2001). https://doi.org/10.1038/85109

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/85109

This article is cited by

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