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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.

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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.).

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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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Supplementary Figure 1 (JPG 78 kb)

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Supplementary Figure 3 (JPG 49 kb)

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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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