Ras signaling pathways mediate NGF-induced enhancement of excitability of small-diameter capsaicin-sensitive sensory neurons from wildtype but not Nf1+/- mice

J. H. Duan, Yue Wang, D. Duarte, M. R. Vasko, G. D. Nicol, C. M. Hingtgen

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

Nerve growth factor (NGF) activates multiple downstream effectors, including Ras, phosphoinositide-3 kinase, and sphingomyelins. However, pathway mediating the NGF-induced augmentation of sensory neuronal excitability remains largely unknown. We previously reported that small-diameter sensory neurons with a heterozygous mutation of the Nf1 gene (Nf1+/-) exhibited increased excitability. The protein product of the Nf1 gene is neurofibromin, a guanosine triphosphatase-activating protein (GAP) for p21ras (Ras) that accelerates the conversion of active Ras-GTP to inactive Ras-GDP. Thus, Nf1+/- cells have augmented basal and stimulated Ras activity. To investigate whether NGF-induced increases in excitability of small-diameter sensory neurons are dependent on Ras signaling, an antibody that blocks the activation of Ras, Y13-259, was perfused into the cell. Under these conditions, the enhanced excitability produced by NGF was suppressed in wildtype neurons but the excitability of Nf1+/- neurons was unaltered. In addition, expression of a dominant-negative form of Ras abolished the ability of NGF to increase the excitability of small-diameter sensory neurons. These results demonstrate that NGF enhances excitability of small-diameter sensory neurons in a Ras-dependent manner while the consequences of decreased expression of neurofibromin cannot be restored by blocking Ras signaling; suggesting that Ras-initiated signaling pathways can regulate both transcriptional and posttranslational control of ion channels important in neuronal excitability.

Original languageEnglish (US)
Pages (from-to)70-74
Number of pages5
JournalNeuroscience Letters
Volume496
Issue number2
DOIs
StatePublished - Jun 1 2011

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Keywords

  • Dorsal root ganglia
  • Nerve growth factor
  • Neurofibromin
  • Sensitization

ASJC Scopus subject areas

  • Neuroscience(all)

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