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.

Truncated TrkB-T1 mediates neurotrophin-evoked calcium signalling in glia cells

Abstract

The neurotrophin receptor TrkB is essential for normal function of the mammalian brain1,2,3. It is expressed in three splice variants. Full-length receptors (TrkBFL) possess an intracellular tyrosine kinase domain and are considered as those TrkB receptors that mediate the crucial effects of brain-derived neurotrophic factor (BDNF) or neurotrophin 4/5 (NT-4/5). By contrast, truncated receptors (TrkB-T1 and TrkB-T2) lack tyrosine kinase activity and have not been reported to elicit rapid intracellular signalling4. Here we show that astrocytes predominately express TrkB-T1 and respond to brief application of BDNF by releasing calcium from intracellular stores. The calcium transients are insensitive to the tyrosine kinase blocker K-252a and persist in mutant mice lacking TrkBFL. By contrast, neurons produce rapid BDNF-evoked signals through TrkBFL and the Nav1.9 channel5,6. Expression of antisense TrkB messenger RNA strongly reduces BDNF-evoked calcium signals in glia. Thus, our results show that, unexpectedly, TrkB-T1 has a direct signalling role in mediating inositol-1,4,5-trisphosphate-dependent calcium release; in addition, they identify a previously unknown mechanism of neurotrophin action in the brain.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: Ca2+ signalling in glia cells evoked by focal application of 0.73 nM (20 ng ml-1) BDNF.
Figure 2: Mechanisms of BDNF-induced glia Ca2+ signals.
Figure 3: Distinct signalling roles of TrkBFL and truncated TrkB receptors in neurons and glia.
Figure 4: BDNF-evoked glia Ca2+ signalling through truncated TrkB-T1 receptors.

Similar content being viewed by others

References

  1. Bonhoeffer, T. Neurotrophins and activity-dependent development of the neocortex. Curr. Opin. Neurobiol. 6, 119–126 (1996)

    Article  CAS  Google Scholar 

  2. Thoenen, H. Neurotrophins and activity-dependent plasticity. Prog. Brain Res. 128, 183–191 (2000)

    Article  CAS  Google Scholar 

  3. Bibel, M. & Barde, Y. A. Neurotrophins: key regulators of cell fate and cell shape in the vertebrate nervous system. Genes Dev. 14, 2919–2937 (2000)

    Article  CAS  Google Scholar 

  4. Patapoutian, A. & Reichardt, L. F. Trk receptors: mediators of neurotrophin action. Curr. Opin. Neurobiol. 11, 272–280 (2001)

    Article  CAS  Google Scholar 

  5. Kafitz, K. W., Rose, C. R., Thoenen, H. & Konnerth, A. Neurotrophin-evoked rapid excitation through TrkB receptors. Nature 401, 918–921 (1999)

    Article  ADS  CAS  Google Scholar 

  6. Blum, R., Kafitz, K. W. & Konnerth, A. Neurotrophin-evoked depolarization requires the sodium channel NaV1.9. Nature 419, 687–693 (2002)

    Article  ADS  CAS  Google Scholar 

  7. Verkhratsky, A., Orkand, R. K. & Kettenmann, H. Glial calcium: homeostasis and signaling function. Physiol. Rev. 78, 99–141 (1998)

    Article  CAS  Google Scholar 

  8. Bezzi, P. & Volterra, A. A neuron-glia signalling network in the active brain. Curr. Opin. Neurobiol. 11, 387–394 (2001)

    Article  CAS  Google Scholar 

  9. Haydon, P. Glia: listening and talking to the synapse. Nature Neurosci. Rev. 2, 185–193 (2001)

    Article  CAS  Google Scholar 

  10. Newman, E. A. Calcium signaling in retinal glial cells and its effect on neuronal activity. Prog. Brain Res. 132, 241–254 (2001)

    Article  CAS  Google Scholar 

  11. Kovalchuk, Y., Hanse, E., Kafitz, K. W. & Konnerth, A. Postsynaptic induction of BDNF-mediated long-term potentiation. Science 295, 1729–1734 (2002)

    Article  ADS  CAS  Google Scholar 

  12. Roback, J. D., Marsh, H. N., Downen, M., Palfrey, H. C. & Wainer, B. H. BDNF-activated signal transduction in rat cortical glial cells. Eur. J. Neurosci. 7, 849–862 (1995)

    Article  CAS  Google Scholar 

  13. Climent, E., Sancho-Tello, M., Minana, R., Barattino, D. & Guerri, C. Astrocytes in culture express the full-length Trk-B receptor and respond to brain derived neurotrophic factor by changing intracellular calcium levels: effect of ethanol exposure in rats. Neurosci. Lett. 288, 53–56 (2000)

    Article  CAS  Google Scholar 

  14. Li, H. S., Xu, X. Z. & Montell, C. Activation of a TRPC3-dependent cation current through the neurotrophin BDNF. Neuron 24, 261–273 (1999)

    Article  CAS  Google Scholar 

  15. Maruyama, T., Kanaji, T., Nakade, S., Kanno, T. & Mikoshiba, K. 2APB, 2-aminoethoxydiphenyl borate, a membrane-penetrable modulator of Ins(1,4,5)P3-induced Ca2+-release. J. Biochem. 122, 498–505 (1997)

    Article  CAS  Google Scholar 

  16. Idestrup, C. P. & Salter, M. W. P2Y and P2U receptors differentially release intracellular Ca2+ via the phospholipase C/inositol 1,4,5-triphosphate pathway in astrocytes from the dorsal spinal cord. Neuroscience 86, 913–923 (1998)

    Article  CAS  Google Scholar 

  17. Smith, R. et al. Receptor-coupled signal transduction in human polymorphonuclear neutrophils: effects of a novel inhibitor of phospholipase C-dependent processes on cell responsiveness. J. Pharmacol. Exp. Ther. 253, 688–697 (1990)

    CAS  Google Scholar 

  18. Helms, J. B. Role of heterotrimeric GTP binding proteins in vesicular protein transport: indications for both classical and alternative G protein cycles. FEBS Lett. 369, 84–88 (1995)

    Article  CAS  Google Scholar 

  19. Hanke, J. H. et al. Discovery of a novel, potent, and Src family-selective tyrosine kinase inhibitor. Study of Lck- and FynT-dependent T cell activation. J. Biol. Chem. 271, 695–701 (1996)

    Article  CAS  Google Scholar 

  20. Barbacid, M. Neurotrophic factors and their receptors. Curr. Opin. Cell Biol. 7, 148–155 (1995)

    Article  CAS  Google Scholar 

  21. Knüsel, B. & Hefti, F. K-252 compounds: modulators of neurotrophin signal transduction. J. Neurochem. 59, 1987–1996 (1992)

    Article  Google Scholar 

  22. Rasmussen, R. in Rapid Cycle Real-time PCR (eds Meuer, S., Wittwer, C. & Nakagawara, K.) 21–34 (Springer, Berlin, 2001)

    Book  Google Scholar 

  23. Klein, R. et al. Targeted disruption of the trkB neurotrophin receptor gene results in nervous system lesions and neonatal death. Cell 75, 113–122 (1993)

    Article  CAS  Google Scholar 

  24. Baxter, G. T. et al. Signal transduction mediated by the truncated trkB receptor isoforms, trkB.T1 and trkB.T2. J. Neurosci. 17, 2683–2690 (1997)

    Article  CAS  Google Scholar 

  25. Hapner, S. J., Boeshore, K. L., Large, T. H. & Lefcort, F. Neural differentiation promoted by truncated trkC receptors in collaboration with p75NTR. Dev. Biol. 201, 90–100 (1998)

    Article  CAS  Google Scholar 

  26. Klein, R., Conway, D., Parada, L. F. & Barbacid, M. The trkB tyrosine protein kinase gene codes for a second neurogenic receptor that lacks the catalytic kinase domain. Cell 61, 647–656 (1990)

    Article  CAS  Google Scholar 

  27. Middlemas, D. S., Lindberg, R. A. & Hunter, T. trkB, a neural receptor protein-tyrosine kinase: evidence for a full-length and two truncated receptors. Mol. Cell. Biol. 1991, 143–153 (1991)

    Article  Google Scholar 

  28. Dechant, G. & Barde, Y. A. The neurotrophin receptor p75(NTR): novel functions and implications for diseases of the nervous system. Nature Neurosci 5, 1131–1136 (2002)

    Article  CAS  Google Scholar 

  29. Kryl, D. & Barker, P. A. TTIP is a novel protein that interacts with the truncated T1 TrkB neurotrophin receptor. Biochem. Biophys. Res. Commun. 279, 925–930 (2000)

    Article  CAS  Google Scholar 

  30. Niwa, H., Yamamura, K. & Miyazaki, J. Efficient selection for high-expression transfectants with a novel eukaryotic vector. Gene 108, 193–199 (1991)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank H. Thoenen for critically discussing the manuscript; T. Hunter for the TrkB cDNA isoforms; J.-i. Miyazaki for pCAGGS and pCAGGS–eGFP; M. Meyer for help with the knockout mice; and I. Schneider, R. Maul and I. Mühlhahn for technical assistance. This work was supported by grants from the Deutsche Forschungsgemeinschaft (to C.R.R. and A.K.).

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Christine R. Rose or Arthur Konnerth.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rose, C., Blum, R., Pichler, B. et al. Truncated TrkB-T1 mediates neurotrophin-evoked calcium signalling in glia cells. Nature 426, 74–78 (2003). https://doi.org/10.1038/nature01983

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature01983

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

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