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.

  • Letter
  • Published:

P/Q-type calcium channels mediate the activity-dependent feedback of syntaxin-1A

Nature volume 401, pages 800–804 (1999)Cite this article

Abstract

Spatial and temporal changes in intracellular calcium concentrations are critical for controlling gene expression in neurons1,2,3,4,5. In many neurons, activity-dependent calcium influx through L-type channels stimulates transcription that depends on the transcription factor CREB by activating a calmodulin-dependent pathway6,7,8,9,10,11. Here we show that selective influx of calcium through P/Q-type channels12,13,14 is responsible for activating expression of syntaxin-1A, a presynaptic protein that mediates vesicle docking, fusion and neurotransmitter release. The initial P/Q-type calcium signal is amplified by release of calcium from intracellular stores and acts through phosphorylation that is dependent on the calmodulin-dependent kinase CaM K II/IV, protein kinase A and mitogen-activated protein kinase kinase. Initiation of syntaxin-1A expression is rapid and short-lived, with syntaxin-1A ultimately interacting with the P/Q-type calcium channel to decrease channel availability. Our results define an activity-dependent feedback pathway that may regulate synaptic efficacy and function in the nervous system.

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: Interaction of syntaxin with α1A P/Q-type channels induces a negative shift in steady-state inactivation (SSI).
Figure 2: Functional α1A P/Q channels stimulate the expression of syntaxin-1A.
Figure 3: Syntaxin-1A expression is stimulated by distinct levels of intracellular Ca2+ and is mediated through activation of Ca2+ stores.
Figure 4: Involvement of second messengers in syntaxin-1A expression.
Figure 5: P/Q-type channels trigger syntaxin-1A expression in cerebellar granule neurons.

Similar content being viewed by others

References

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

    Article  ADS  CAS  Google Scholar 

  2. Bito,H., Deisseroth,K. & Tsien,R. W. Ca2+-dependent regulation in neuronal gene expression. Curr. Opin. Neurobiol. 7, 419–429 (1997).

    Article  CAS  Google Scholar 

  3. 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  ADS  CAS  Google Scholar 

  4. Dolmetsch,R. E., Lewis,R. S., Goodnow,C. C. & Healy,J. I. Differential activation of transcription factors induced by Ca2+ response amplitude and duration. Nature 386, 855–858 (1997).

    Article  ADS  CAS  Google Scholar 

  5. Li,W., Llopis,J., Whitney,M., Zlokarnik,G. & Tsien,R. Y. Cell-permeant caged InsP3 ester shows that Ca2+ spike frequency can optimize gene expression. Nature 392, 936–941 (1998).

    Article  ADS  CAS  Google Scholar 

  6. 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  ADS  CAS  Google Scholar 

  7. Deisseroth,K., Bito,H. & Tsien,R. W. Signalling from synapse to nucleus: postsynaptic CREB phosphorylation during multiple forms of hippocampal synaptic plasticity. Neuron 16, 89–101 (1996).

    Article  CAS  Google Scholar 

  8. 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 

  9. Diesseroth,K., Heist,E. K. & Tsien,R. W. Translocation of calmodulin to the nucleus supports CREB phosphorylation in hippocampal neurons. Nature 392, 198–202 (1998).

    Article  ADS  Google Scholar 

  10. 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 

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

    Article  CAS  Google Scholar 

  12. Llina,R., Sugimori,M., Lin,J. W. & Cherksey,B. Blocking and isolation of a calcium channel from neurons in mammals and cephalopods utilizing a toxin fraction (FTX) from funnel-web spider poison. Proc. Natl Acad. Sci. USA 86, 1689–1693 (1989).

    Article  ADS  Google Scholar 

  13. Mintz,I. M., Adams,M. E. & Bean,B. P. P-type calcium channels in rat central and peripheral neurons. Neuron 9, 85–95 (1992).

    Article  CAS  Google Scholar 

  14. Bourinet,E. et al. Splicing of α1A subunit gene generates phenotypic variants of P- and Q-type calcium channels. Nature Neurosci. 2, 407–415 (1999).

    Article  CAS  Google Scholar 

  15. Betz,A., Okamoto,M., Benseler,F. & Brose,N. Direct interaction of the rat unc-13 homologue munc13-1 with the N-terminus of syntaxin. J. Biol. Chem. 272, 2520–2526 (1997).

    Article  CAS  Google Scholar 

  16. Pevsner,J. et al. Specificity and regulation of a synaptic vesicle docking complex. Neuron 13, 353–361 (1994).

    Article  CAS  Google Scholar 

  17. Fujita, Y. et al. Tomosyn: a syntaxin-1-binding protein that forms a novel complex in the neurotransmitter release process. Neuron 20, 905–915 (1998).

    Article  Google Scholar 

  18. Sheng,Z.-H., Westenbroek,R. E. & Catterall,W. A. Physical link and functional coupling of presynaptic calcium channels and the synaptic vesicle docking/fusion machinery. J. Bioenerg. Biomembr. 30, 335–345 (1998).

    Article  CAS  Google Scholar 

  19. Sheng,Z.-H., Rettig,J., Takahashi,M. & Catterall,W. A. Identification of a syntaxin-binding site on N-type calcium channels. Neuron 13, 1303–1313 (1994).

    Article  CAS  Google Scholar 

  20. Bezprozvanny,I., Scheller,R. H. & Tsien,R. W. Functional impact of syntaxin on gating of N-type and Q-type calcium channels. Nature 378, 623–626 (1995).

    Article  ADS  CAS  Google Scholar 

  21. Martin-Moutot,N. et al. Interaction of SNARE complexes with P/Q-type calcium channels in rat cerebellar synaptosomes. J. Biol. Chem. 271, 6567–6570 (1996).

    Article  CAS  Google Scholar 

  22. Rettig,J. et al. Isoform-specific interaction of the α1A subunits of brain Ca2+ channels with the presynaptic proteins syntaxin and SNAP-25. Proc. Natl Acad. Sci. USA 93, 7363–7368 (1996).

    Article  ADS  CAS  Google Scholar 

  23. Kim,D. K. & Catterall,W. A. Ca2+-dependent and -independent interactions of the isoforms of the α1A subunit of brain Ca2+ channels with presynaptic SNARE proteins. Proc. Natl Acad. Sci. USA 94, 14782–14786 (1997).

    Article  ADS  CAS  Google Scholar 

  24. Williamson,L. C., Halpern,J. L., Montecucco,C., Brown,J. E. & Neale,E. A. Clostridial neurotoxins and substrate proteolysis in intact neurons: botulinum neurotoxin C acts on synaptosomal-associated protein of 25 kDa. J. Biol. Chem. 271, 7694–7699 (1996).

    Article  CAS  Google Scholar 

  25. Honer,W. G., Hu,L, & Davies,P. Human synaptic proteins with a heterogenous distribution in cerebellum and visual cortex. Brain Res. 609, 9–20 (1993).

    Article  CAS  Google Scholar 

  26. Daly,C. & Ziff,E. B. Post-transcriptional regulation of synaptic vesicle protein expression and the developmental control of synaptic vesicle formation. J. Neurosci. 17, 2365–2375 (1997).

    Article  CAS  Google Scholar 

  27. Gafni,J. et al. Xestospongins: potent membrane permeable blockers of the inositol 1,4,5-trisphosphate receptor. Neuron 19, 723–733 (1997).

    Article  CAS  Google Scholar 

  28. Gonzalez,G. A. & Montminy,M. R. Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133. Cell 59, 675–680 (1989).

    Article  CAS  Google Scholar 

  29. 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 

  30. Carrion,A. M., Link,W. A., Ledo,F., Mellstrom,B. & Naranjo,J. R. DREAM is a Ca2+-regulated transcriptional repressor. Nature 398, 80–84 (1999).

    Article  ADS  CAS  Google Scholar 

Download references

Acknowledgements

We thank M. Gilbert, C. Santi, A. Stea and G. Zamponi for comments and discussions. We also thank W. Honer for providing the SP8 human syntaxin-1A monoclonal antibody and D. Brink and V. Leuranguer for tissue culture support. The research was supported by grants from the Medical Research Council (MRC) of Canada (T.P.S. and T.H.M.), postdoctoral support from the Amyotrophic Lateral Sclerosis Society of Canada (K.S.), and studentship and postdoctoral fellowship support from the MRC (H.G. and J.M., respectively). T.P.S. and T.H.M. are recipients of MRC of Canada Scientist awards.

Author information

Author notes

  1. Kathy G. Sutton, John E. McRory and Timothy H. Murphy: These authors contributed equally to this work.

Authors and Affiliations

  1. Biotechnology Laboratory and Dept Psychiatry University of British Columbia, Vancouver, V6T 1Z3, Canada

    Kathy G. Sutton, John E. McRory, Heather Guthrie & Terrance P. Snutch

  2. Kinsmen Laboratory of Neurological Research, Dept Psychiatry University of British Columbia, Vancouver, V6T 1Z3, Canada

    Timothy H. Murphy

Authors
  1. Kathy G. Sutton
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. John E. McRory
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Heather Guthrie
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Timothy H. Murphy
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Terrance P. Snutch
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Terrance P. Snutch.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sutton, K., McRory, J., Guthrie, H. et al. P/Q-type calcium channels mediate the activity-dependent feedback of syntaxin-1A. Nature 401, 800–804 (1999). https://doi.org/10.1038/44586

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/44586

This article is cited by

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