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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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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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