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Neurotrophin-evoked depolarization requires the sodium channel NaV1.9

Abstract

Brain-derived neurotrophic factor (BDNF) and other neurotrophins are essential for normal brain function. Many types of neurons in the central nervous system are excited by BDNF or neurotrophin-4/5, an action that has recently been implicated in synaptic plasticity. The mechanisms involved in this transmitter-like action of neurotrophins remains unclear. Here, by screening candidate genes with an antisense messenger RNA expression approach and by co-expressing the receptor tyrosine kinase TrkB and various sodium channels, we demonstrate that the tetrodotoxin-insensitive sodium channel NaV1.9 underlies the neurotrophin-evoked excitation. These results establish the molecular basis of neurotrophin-evoked depolarization and reveal a mechanism of ligand-mediated sodium channel activation.

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Figure 1: Pharmacological properties of the BDNF-evoked inward current (INa).
Figure 2: TrkB is required for BDNF-evoked INa in SH-SY5Y cells.
Figure 3: NaV1.9 is required for BDNF-evoked INa in SH-SY5Y cells.
Figure 4: Reconstitution of BDNF-evoked INa in HEK-293 cells.
Figure 5: Comparison of reconstituted and neuronal BDNF-evoked INa.
Figure 6: NaV1.9 is required for BDNF-evoked INa in hippocampal neurons.

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References

  1. Barbacid, M. The Trk family of neurotrophin receptors. J. Neurobiol. 25, 1386–1403 (1994)

    Article  CAS  Google Scholar 

  2. Lewin, G. R. & Barde, Y. A. Physiology of the neurotrophins. Annu. Rev. Neurosci. 19, 289–317 (1996)

    Article  CAS  Google Scholar 

  3. Kaplan, D. R. & Miller, F. D. Neurotrophin signal transduction in the nervous system. Curr. Opin. Neurobiol. 10, 381–391 (2000)

    Article  CAS  Google Scholar 

  4. Huang, E. J. & Reichardt, L. F. Neurotrophins: roles in neuronal development and function. Annu. Rev. Neurosci. 24, 677–736 (2001)

    Article  CAS  Google Scholar 

  5. Thoenen, H. Neurotrophins and neuronal plasticity. Science 270, 593–598 (1995)

    Article  ADS  CAS  Google Scholar 

  6. Kohara, K., Kitamura, A., Morishima, M. & Tsumoto, T. Activity-dependent transfer of brain-derived neurotrophic factor to postsynaptic neurons. Science 291, 2419–2423 (2001)

    Article  ADS  CAS  Google Scholar 

  7. Hartmann, M., Heumann, R. & Lessmann, V. Synaptic secretion of BDNF after high-frequency stimulation of glutamatergic synapses. EMBO J. 20, 5887–5897 (2001)

    Article  CAS  Google Scholar 

  8. Poo, M. M. Neurotrophins as synaptic modulators. Nature Rev. Neurosci. 2, 24–32 (2001)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  10. Schuman, E. M. Neurotrophin regulation of synaptic transmission. Curr. Opin. Neurobiol. 9, 105–109 (1999)

    Article  CAS  Google Scholar 

  11. Kang, H., Welcher, A. A., Shelton, D. & Schuman, E. M. Neurotrophins and time: different roles for TrkB signaling in hippocampal long-term potentiation. Neuron 19, 653–664 (1997)

    Article  CAS  Google Scholar 

  12. Figurov, A., Pozzo-Miller, L. D., Olafsson, P., Wang, T. & Lu, B. Regulation of synaptic responses to high-frequency stimulation and LTP by neurotrophins in the hippocampus. Nature 381, 706–709 (1996)

    Article  ADS  CAS  Google Scholar 

  13. 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 

  14. Korte, M. et al. Virus-mediated gene transfer into hippocampal CA1 region restores long-term potentiation in brain-derived neurotrophic factor mutant mice. Proc. Natl Acad. Sci. USA 93, 12547–12552 (1996)

    Article  ADS  CAS  Google Scholar 

  15. Patterson, S. L. et al. Recombinant BDNF rescues deficits in basal synaptic transmission and hippocampal LTP in BDNF knockout mice. Neuron 16, 1137–1145 (1996)

    Article  CAS  Google Scholar 

  16. Minichiello, L. et al. Essential role for TrkB receptors in hippocampus-mediated learning. Neuron 24, 401–414 (1999)

    Article  CAS  Google Scholar 

  17. Xu, B. et al. The role of brain-derived neurotrophic factor receptors in the mature hippocampus: modulation of long-term potentiation through a presynaptic mechanism involving TrkB. J. Neurosci. 20, 6888–6897 (2000)

    Article  CAS  Google Scholar 

  18. 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 

  19. 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 

  20. Dib-Hajj, S. D., Tyrrell, L., Black, J. A. & Waxman, S. G. NaN, a novel voltage-gated Na channel, is expressed preferentially in peripheral sensory neurons and down-regulated after axotomy. Proc. Natl Acad. Sci. USA 95, 8963–8968 (1998)

    Article  ADS  CAS  Google Scholar 

  21. Goldin, A. L. et al. Nomenclature of voltage-gated sodium channels. Neuron 28, 365–368 (2000)

    Article  CAS  Google Scholar 

  22. Dib-Hajj, S. D. et al. Two tetrodotoxin-resistant sodium channels in human dorsal root ganglion neurons. FEBS Lett. 462, 117–120 (1999)

    Article  ADS  CAS  Google Scholar 

  23. Jeong, S. Y. et al. Identification of a novel human voltage-gated sodium channel alpha subunit gene, SCN12A. Biochem. Biophys. Res. Commun. 267, 262–270 (2000)

    Article  CAS  Google Scholar 

  24. Favre, I., Moczydlowski, E. & Schild, L. Specificity for block by saxitoxin and divalent cations at a residue which determines sensitivity of sodium channel subtypes to guanidinium toxins. J. Gen. Physiol. 106, 203–229 (1995)

    Article  CAS  Google Scholar 

  25. Hoehn, K., Watson, T. W. & MacVicar, B. A. A novel tetrodotoxin-insensitive, slow sodium current in striatal and hippocampal neurons. Neuron 10, 543–552 (1993)

    Article  CAS  Google Scholar 

  26. Kaplan, D. R., Matsumoto, K., Lucarelli, E. & Thiele, C. J. Induction of TrkB by retinoic acid mediates biologic responsiveness to BDNF and differentiation of human neuroblastoma cells. Neuron 11, 321–331 (1993)

    Article  CAS  Google Scholar 

  27. Encinas, M. et al. Sequential treatment of SH-SY5Y cells with retinoic acid and brain-derived neurotrophic factor gives rise to fully differentiated, neurotrophic factor-dependent, human neuron-like cells. J. Neurochem. 75, 991–1003 (2000)

    Article  CAS  Google Scholar 

  28. Catterall, W. A. From ionic currents to molecular mechanisms: the structure and function of voltage-gated sodium channels. Neuron 26, 13–25 (2000)

    Article  CAS  Google Scholar 

  29. Penzotti, J. L., Fozzard, H. A., Lipkind, G. M. & Dudley, S. C. Differences in saxitoxin and tetrodotoxin binding revealed by mutagenesis of the Na+ channel outer vestibule. Biophys. J. 75, 2647–2657 (1998)

    Article  CAS  Google Scholar 

  30. Noda, M. et al. Existence of distinct sodium channel messenger RNAs in rat brain. Nature 320, 188–192 (1986)

    Article  ADS  CAS  Google Scholar 

  31. Kayano, T., Noda, M., Flockerzi, V., Takahashi, H. & Numa, S. Primary structure of rat brain sodium channel III deduced from the cDNA sequence. FEBS Lett. 228, 187–194 (1988)

    Article  CAS  Google Scholar 

  32. Klugbauer, N., Lacinova, L., Flockerzi, V. & Hofmann, F. Structure and functional expression of a new member of the tetrodotoxin-sensitive voltage-activated sodium channel family from human neuroendocrine cells. EMBO J. 14, 1084–1090 (1995)

    Article  CAS  Google Scholar 

  33. Satin, J. et al. A mutant of TTX-resistant cardiac sodium channels with TTX-sensitive properties. Science 256, 1202–1205 (1992)

    Article  ADS  CAS  Google Scholar 

  34. 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 

  35. Kossel, A. H., Cambridge, S. B., Wagner, U. & Bonhoeffer, T. A caged Ab reveals an immediate/instructive effect of BDNF during hippocampal synaptic potentiation. Proc. Natl Acad. Sci. USA 98, 14702–14707 (2001)

    Article  ADS  CAS  Google Scholar 

  36. Patterson, S. L. et al. Some forms of cAMP-mediated long-lasting potentiation are associated with release of BDNF and nuclear translocation of phospho-MAP kinase. Neuron 32, 123–140 (2001)

    Article  CAS  Google Scholar 

  37. Kafitz, K. W., Lepier, A., Thoenen, H. & Konnerth, A. Saxitoxin-sensitivity of neurotrophin-induced rapid excitation and neurite growth. Pfluegers Arch. 441, R125 (2001)

    Google Scholar 

  38. McAllister, A. K., Katz, L. C. & Lo, D. C. Neurotrophin regulation of cortical dendritic growth requires activity. Neuron 17, 1057–1064 (1996)

    Article  CAS  Google Scholar 

  39. Tate, S. et al. Two sodium channels contribute to the TTX-R sodium current in primary sensory neurons. Nature Neurosci. 1, 653–655 (1998)

    Article  CAS  Google Scholar 

  40. Coward, K. et al. Immunolocalization of SNS/PN3 and NaN/SNS2 sodium channels in human pain states. Pain 85, 41–50 (2000)

    Article  CAS  Google Scholar 

  41. Yiangou, Y., Birch, R., Sangameswaran, L., Eglen, R. & Anand, P. SNS/PN3 and SNS2/NaN sodium channel-like immunoreactivity in human adult and neonate injured sensory nerves. FEBS Lett. 467, 249–252 (2000)

    Article  CAS  Google Scholar 

  42. Herzog, R. I., Cummins, T. R. & Waxman, S. G. Persistent TTX-tesistant Na+ current affects resting potential and response to depolarization in simulated spinal sensory neurons. J. Neurophysiol. 86, 1351–1364 (2001)

    Article  CAS  Google Scholar 

  43. Liu, C., Dib-Hajj, S. D. & Waxman, S. G. Fibroblast growth factor homologous factor 1B binds to the C terminus of the tetrodotoxin-resistant sodium channel rNav1.9a (NaN). J. Biol. Chem. 276, 18925–18933 (2001)

    Article  CAS  Google Scholar 

  44. Cummins, T. R. et al. A novel persistent tetrodotoxin-resistant sodium current in SNS-null and wild-type small primary sensory neurons. J. Neurosci. 19, RC43, 1–6 (1999)

    Article  Google Scholar 

  45. Okuse, K. et al. Annexin II light chain regulates sensory neuron-specific sodium channel expression. Nature 417, 653–656 (2002)

    Article  ADS  CAS  Google Scholar 

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Acknowledgements

We thank H. Thoenen, O. Garaschuk and C. Rose for comments on early versions of the manuscript; I. Schneider, R. Maul and I. Mühlhahn for technical assistance; N. Klugbauer and F. Hofmann for the pcDNA3a NaV1.7 (hNE-Na) plasmid; J.-i. Miyazaki for the pCAGGS and pCAGGS-eGFP vectors; and A. Lepier for helpful discussions. This study was supported by grants from the Deutsche Forschungsgemeinschaft and the German–Israeli Foundation, and in part by funds of the Leibniz Prize and the Max Planck Prize to A.K.

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Correspondence to Arthur Konnerth.

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Blum, R., Kafitz, K. & Konnerth, A. Neurotrophin-evoked depolarization requires the sodium channel NaV1.9. Nature 419, 687–693 (2002). https://doi.org/10.1038/nature01085

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