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


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.

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  1. 1

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

  2. 2

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

  3. 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)

  4. 4

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

  5. 5

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

  6. 6

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

  7. 7

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

  8. 8

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

  9. 9

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

  10. 10

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

  11. 11

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

  12. 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)

  13. 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)

  14. 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)

  15. 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)

  16. 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)

  17. 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)

  18. 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)

  19. 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)

  20. 20

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

  21. 21

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

  22. 22

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

  23. 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)

  24. 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)

  25. 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)

  26. 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)

  27. 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)

  28. 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)

  29. 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)

  30. 30

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

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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.).

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Correspondence to Christine R. Rose or Arthur Konnerth.

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The authors declare that they have no competing financial interests.

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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.


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