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:

Calcium channel activation stabilizes a neuronal calcium channel mRNA

Nature Neuroscience volume 2, pages 785–790 (1999)Cite this article

Abstract

We have identified a calcium-dependent pathway in neurons that regulates expression levels of the α1B subunit and N channel current. When neurons are depolarized and voltage-gated calcium channels activated, the half-life of cellular N channel α1B mRNA is prolonged. This stabilizing effect of depolarization is mediated through the 3′ untranslated region of a long form of the α1B mRNA and may represent a form of modulation of N-channel levels that does not require changes in gene transcription. Increases in N channel expression would affect several key neuronal functions controlled by calcium, including transmitter release and neurite outgrowth.

Access through your institution
Buy or subscribe

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

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Figure 1: Forms of α1B message and their decay in vitro (a) Functionally important sites within the 3′ untranslated region of the Ca2+-channel α1B message.
Figure 2: The long form of α1B mRNA was stabilized by depolarization.
Figure 3: Nimodipine inhibits depolarization-induced stabilization of the long form of the α1B mRNA in sympathetic neurons.
Figure 4: Potassium-induced depolarization slows degradation of the long form of α1B mRNA in sympathetic neurons in the presence of Actinomycin D.
Figure 5: Depolarization-induced increases in the N-type Ca2+ channel current density and levels of the α1B subunit in sympathetic neurons maintained in culture.
Figure 6: A comparison of the destabilizing effects of the short and long 3′ untranslated regions on a reporter mRNA in a cell-free degradation assay33.

Similar content being viewed by others

References

  1. Dunlap, K., Luebke, J. I. & Turner, T. J. Exocytotic Ca2+ channels in mammalian central neurons. Trends Neurosci. 18, 89–98 (1995).

    Article  CAS  Google Scholar 

  2. Komuro, H. & Rakic, P. Selective role of N-type calcium channels in neuronal migration. Science 257, 806–809 (1992).

    Article  CAS  Google Scholar 

  3. Rusanescu, G., Qi, H., Thomas, S. M., Brugge, J. S. & Halegoua, S. Calcium influx induces neurite growth through a Src-Ras signaling cassette. Neuron 15, 1415–1425 (1995).

    Article  CAS  Google Scholar 

  4. Greenberg, M. E., Ziff, E. B. & Greene, L. A. Stimulation of neuronal acetylcholine receptors induces rapid gene transcription. Science 234, 80–83 (1986).

    Article  CAS  Google Scholar 

  5. Morgan, J. I. & Curran, T. Role of ion flux in the control of c-fos expression. Nature 322, 552–555 (1986).

    Article  CAS  Google Scholar 

  6. Murphy, T. H., Worley, P. F. & Baraban, J. M. L-type voltage-sensitive calcium channels mediate synaptic activation of immediate early genes. Neuron 7, 625–635 (1991).

    Article  CAS  Google Scholar 

  7. Kirsch, J. & Betz, H. Glycine-receptor activation is required for receptor clustering in spinal neurons. Nature 392, 717–720 (1998).

    Article  CAS  Google Scholar 

  8. Tsien, R. W., Lipscombe, D., Madison, D. V., Bley, K. R. & Fox, A. P. Multiple types of neuronal calcium channels and their selective modulation. Trends Neurosci. 11, 431–438 (1988).

    Article  CAS  Google Scholar 

  9. Plummer, M. R., Logothetis, D. E. & Hess, P. Elementary properties and pharmacological sensitivities of calcium channels in mammalian peripheral neurons. Neuron 2, 1453–1463 (1989).

    Article  CAS  Google Scholar 

  10. Hille, B. Modulation of ion-channel function by G-protein-coupled receptors. Trends Neurosci. 17, 531–536 (1994).

    Article  CAS  Google Scholar 

  11. Diverse-Pierluissi, M., Goldsmith, P. K. & Dunlap, K. Transmitter-mediated inhibition of N-type calcium channels in sensory neurons involves multiple GTP-binding proteins and subunits. Neuron 14, 191–200 (1995).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  13. De Koninck, P. & Cooper, E. Differential regulation of neuronal nicotinic ACh receptor subunit genes in cultured neonatal rat sympathetic neurons: specific induction of alpha 7 by membrane depolarization through a Ca2+/calmodulin-dependent kinase pathway. J. Neurosci. 15, 7966–7978 (1995).

  14. Shieh, P. B., Hu, S. C., Bobb, K., Timmusk, T. & Ghosh, A. Identification of a signaling pathway involved in calcium regulation of BDNF expression. Neuron 20, 727–740 (1998).

    Article  CAS  Google Scholar 

  15. Tao, X., Finkbeiner, S., Arnold, D. B., Shaywitz, A. J. & Greenberg, M. E. Ca2+ influx regulates BDNF transcription by a CREB family transcription factor-dependent mechanism. Neuron 20, 709–726 (1998).

    Article  CAS  Google Scholar 

  16. Sheng, M. E., Thompson, M. A. & Greenberg, M. E. CREB: a Ca(2+)-regulated transcription factor phosphorylated by calmodulin-dependent kinases. Science 252, 1427–1430 (1991).

    Article  CAS  Google Scholar 

  17. Dubel, S. J. et al. Molecular cloning of the alpha-1 subunit of an omega-conotoxin-sensitive calcium channel. Proc. Natl. Acad. Sci. USA 89, 5058–5062 (1992).

    Article  CAS  Google Scholar 

  18. Williams, M. E. et al. Structure and functional expression of an omega-conotoxin-sensitive human N-type calcium channel. Science 257, 389–395 (1992).

    Article  CAS  Google Scholar 

  19. Fujita, Y. et al. Primary structure and functional expression of the omega-conotoxin-sensitive N-type calcium channel from rabbit brain. Neuron 10, 585–598 (1993).

    Article  CAS  Google Scholar 

  20. Lin, Z., Haus, S., Edgerton, J. & Lipscombe, D. Identification of functionally distinct isoforms of the N-type Ca2+ channel in rat sympathetic ganglia and brain. Neuron 18, 153–166 (1997).

    Article  CAS  Google Scholar 

  21. Lin, Z. et al. Alternative splicing of a short cassette exon in α1B generates functionally distinct N-type calcium channels in central and peripheral neurons. J. Neurosci. 19, 5322–5331 (1999).

    Article  CAS  Google Scholar 

  22. Coppola, T. et al. Molecular cloning of a murine N-type calcium channel alpha 1 subunit. Evidence for isoforms, brain distribution, and chromosomal localization. FEBS Lett. 338, 1–5 (1994).

    Article  CAS  Google Scholar 

  23. Hepler, J. E., Van Wyk, J. J. & Lund, P. K. Different half-lives of insulin-like growth factor I mRNAs that differ in length of 3′ untranslated sequence. Endocrinology 127, 1550–1552 (1990).

    Article  CAS  Google Scholar 

  24. Chen, C. Y. & Shyu, A. B. AU-rich elements: characterization and importance in mRNA degradation. Trends Biochem. Sci. 20, 465–470 (1995).

    Article  CAS  Google Scholar 

  25. Tsai, K. C., Cansino, V. V., Kohn, D. T., Neve, R. L. & Perrone-Bizzozero, N. I. Post-transcriptional regulation of the GAP-43 gene by specific sequences in the 3′ untranslated region of the mRNA. J. Neurosci. 17, 1950–1958 (1997).

    Article  CAS  Google Scholar 

  26. Wahle, E. & Keller, W. The biochemistry of polyadenylation. Trends Biochem. Sci. 21, 247–250 (1996).

    Article  CAS  Google Scholar 

  27. Lin, Z., Harris, C. & Lipscombe, D. The molecular identity of Ca2+ channel α1-subunits expressed in rat sympathetic neurons. J. Mol. Neurosci. 7, 257–267 (1996).

    Article  CAS  Google Scholar 

  28. Brosenitsch, T. A., Salgado-Commissariat, D., Kunze, D. L. & Katz, D. M. A role for L-type calcium channels in developmental regulation of transmitter phenotype in primary sensory neurons. J. Neurosci. 18, 1047–1055 (1998).

    Article  CAS  Google Scholar 

  29. Tolon, R. M., Sanchez Franco, F., de los Frailes, M. T., Lorenzo, M. J. & Cacicedo, L. Effect of potassium-induced depolarization on somatostatin gene expression in cultured fetal rat cerebrocortical cells. J. Neurosci. 14, 1053–1059 (1994).

    Article  CAS  Google Scholar 

  30. Luo, Z., Fuentes, M. E. & Taylor, P. Regulation of acetylcholinesterase mRNA stability by calcium during differentiation from myoblasts to myotubes. J. Biol. Chem. 269, 27216–27223 (1994).

    CAS  PubMed  Google Scholar 

  31. McCarthy, R. T. & TanPiengco, P. Multiple types of high-threshold calcium channels in rabbit sensory neurons: high-affinity block of neuronal L-type by nimodipine. J. Neurosci. 12, 2225–2234 (1992).

    Article  CAS  Google Scholar 

  32. Ross, J. mRNA stability in mammalian cells. Microbiol. Rev. 59, 423–450 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Chu, W., Presky, D. H., Swerlick, R. A. & Burns, D. K. Alternatively processed human E-selectin transcripts linked to chronic expression of E-selectin in vivo. J. Immunol. 153, 4179–4189 (1994).

    CAS  PubMed  Google Scholar 

  34. Treisman, R. Transient accumulation of c-fos RNA following serum stimulation requires a conserved 5′ element and c-fos 3′ sequences. Cell 42, 889–902 (1985).

    Article  CAS  Google Scholar 

  35. Shaw, G. & Kamen, R. A. Conserved AU sequence from the 3′ untranslated region of GM-CSF mRNA mediates selective mRNA degradation. Cell 46, 659–667 (1986).

    Article  CAS  Google Scholar 

  36. Stoecklin, G., Hahn, S. & Moroni, C. Functional hierarchy of AUUUA motifs in mediating rapid interleukin-3 mRNA decay. J. Biol. Chem. 269, 28591–28597 (1994).

    CAS  PubMed  Google Scholar 

  37. Gao, F. B. Messenger RNAs in dendrites: localization, stability, and implications for neuronal function. Bioessays 20, 70–78 (1998).

    Article  CAS  Google Scholar 

  38. Wodnar-Filipowicz, A. & Moroni, C. Regulation of interleukin 3 mRNA expression in mast cells occurs at the posttranscriptional level and is mediated by calcium ions. Proc. Natl. Acad. Sci. USA 87, 777–781 (1990).

    Article  CAS  Google Scholar 

  39. Iwai, Y., Akahane, K., Pluznik, D. H. & Cohen, R. B. Ca2+ ionophore A23187-dependent stabilization of granulocyte-macrophage colony-stimulating factor messenger RNA in murine thymoma EL-4 cells is mediated through two distinct regions in the 3′-untranslated region. J. Immunol. 150, 4386–4394 (1993).

    CAS  PubMed  Google Scholar 

  40. Sachs, A. B. Messenger RNA degradation in eukaryotes. Cell 74, 413–421 (1993).

    Article  CAS  Google Scholar 

  41. Ross J. Control of messenger RNA stability in higher eukaryotes. Trends Genet. 12, 171–175 (1996).

    Article  CAS  Google Scholar 

  42. Crino, P. B. & Eberwine, J. Molecular characterization of the dendritic growth cone: regulated mRNA transport and local protein synthesis. Neuron 17, 1173–1187 (1996).

    Article  CAS  Google Scholar 

  43. Davis, L., Dou, P., DeWit, M. & Kater, S. B. Protein synthesis within neuronal growth cones. J. Neurosci. 12, 4867–4877 (1992).

    Article  CAS  Google Scholar 

  44. Steward, O. & Banker, G. A. Getting the message from the gene to the synapse: sorting and intracellular transport of RNA in neurons. Trends Neurosci. 15, 180–186 (1992).

    Article  CAS  Google Scholar 

  45. Lipscombe, D. et al. Spatial distribution of calcium channels and cytosolic calcium transients in growth cones and cell bodies of sympathetic neurons. Proc. Natl. Acad. Sci. USA 85, 2398–2402 (1988).

    Article  CAS  Google Scholar 

  46. Westenbroek, R. E. et al. Biochemical properties and subcellular distribution of an N-type calcium channel alpha 1 subunit. Neuron 9, 1099–1115 (1992).

    Article  CAS  Google Scholar 

  47. Mills, L. R. et al. N-type Ca2+ channels are located on somata, dendrites, and a subpopulation of dendritic spines on live hippocampal pyramidal neurons. J. Neurosci. 14, 6815–6824 (1994).

    Article  CAS  Google Scholar 

  48. Elliott, E. M., Malouf, A. T. & Catterall, W. A. Role of calcium channel subtypes in calcium transients in hippocampal CA3 neurons. J. Neurosci. 15, 6433–6444 (1995).

    Article  CAS  Google Scholar 

  49. Kavalali, E. T., Zhuo, M., Bito, H. & Tsien, R. W. Dendritic Ca2+ channels characterized by recordings from isolated hippocampal dendritic segments. Neuron 18, 651–663 (1997).

    Article  CAS  Google Scholar 

  50. Vance, C. L. et al. Differential expression and association of calcium channel alpha1B and beta subunits during rat brain ontogeny. J. Biol. Chem. 273, 14495–14502 (1998).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Terry Snutch and Steve Dubel for providing unpublished partial 3′UTR sequence of rbB-I. We are also grateful to Leslie Tolerico, Justin Fallon and Betsy Quinlin for reading the manuscript. This work was done in partial fulfillment of the requirements for a Ph.D. degree from Brown University (S.S.). Supported by NS 29967 and NS 01927 (D.L.) and Training Grant MH19118.

Author information

Author notes

  1. Zhixin Lin

    Present address: Cold Spring Harbor Laboratory, Beckman Building, 1 Bungtown Rd., Cold Spring Harbor, New York, 11724, USA

Authors and Affiliations

  1. Department of Neuroscience, Brown University, 192 Thayer Street, Box 1953, Providence, 02912, Rhode Island, USA

    Stephanie Schorge, Seema Gupta, Zhixin Lin & Diane Lipscombe

  2. Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, 44106, Ohio, USA

    Maureen W. McEnery

Authors
  1. Stephanie Schorge
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Seema Gupta
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Zhixin Lin
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Maureen W. McEnery
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Diane Lipscombe
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Diane Lipscombe.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schorge, S., Gupta, S., Lin, Z. et al. Calcium channel activation stabilizes a neuronal calcium channel mRNA. Nat Neurosci 2, 785–790 (1999). https://doi.org/10.1038/12153

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/12153

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