Differential role of GDNF and NGF in the maintenance of two TTX- resistant sodium channels in adult DRG neurons

Jenny Fjell, Theodore R. Cummins, Sulayman D. Dib-Hajj, Kaj Fried, Joel A. Black, Stephen G. Waxman

Research output: Contribution to journalArticle

176 Scopus citations

Abstract

Following sciatic nerve transection, the electrophysiological properties of small dorsal root ganglion (DRG) neurons are markedly altered, with attenuation of TTX-R sodium currents and the appearance of rapidly repriming TTX-S currents. The reduction in TTX-R currents has been attributed to a down-regulation of sodium channels SNS/PN3 and NaN. While infusion of exogenous NGF to the transected nerve restores SNS/PN3 transcripts to near- normal levels in small DRG neurons, TTX-R sodium currents are only partially rescued. Binding of the isolectin IB4 distinguishes two subpopulations of small DRG neurons: IB4+ neurons, which express receptors for the GDNF family of neurotrophins, and IB4- neurons that predominantly express TrkA. We show here that SNS/PN3 is expressed in approximately one-half of both IB4+ and IB4- DRG neurons, while NaN is preferentially expressed in IB4+ neurons. Whole-cell patch-clamp studies demonstrate that TTX-R sodium currents in IB4+ neurons have a more hyperpolarized voltage-dependence of activation and inactivation than do IB4- neurons, suggesting different electrophysiological properties for SNS/PN3 and NaN. We confirm that NGF restores SNS/PN3 mRNA levels in DRG neurons in vitro and demonstrate that the trk antagonist K252a blocks this rescue. The down-regulation of NaN mRNA is, nevertheless, not rescued by NGF-treatment in either IB4+ or IB4- neurons and NGF-treatment in vitro does not significantly increase the peak amplitude of the TTX-R current in small DRG neurons. In contrast, GDNF-treatment causes a twofold increase in the peak amplitude of TTX-R sodium currents and restores both SNS/PN3 and NaN mRNA to near-normal levels in IB4+ neurons. These observations provide a mechanism for the partial restoration of TTX-R sodium currents by NGF in axotomized DRG neurons, and demonstrate that the neurotrophins NGF and GDNF differentially regulate sodium channels SNS/PN3 and NaN.

Original languageEnglish (US)
Pages (from-to)267-282
Number of pages16
JournalMolecular Brain Research
Volume67
Issue number2
DOIs
StatePublished - Apr 20 1999
Externally publishedYes

Keywords

  • Dorsal root ganglia
  • GDNF
  • IB4
  • Ion channel
  • NGF
  • NaN
  • SNS/PN3

ASJC Scopus subject areas

  • Molecular Biology
  • Cellular and Molecular Neuroscience

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