title: Ras signaling pathways mediate NGF-induced enhancement of excitability of small-diameter capsaicin-sensitive sensory neurons from wildtype but not Nf1+/- mice.
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.
authors.affiliation: Department of Pharmacology and Toxicology, School of Medicine, Indiana University, Indianapolis, IN 46202, United States.
authors.forename: J-H
authors.initials: JH
authors.lastname: Duan
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.forename: D
authors.initials: D
authors.lastname: Duarte
authors.forename: M R
authors.initials: MR
authors.lastname: Vasko
authors.forename: G D
authors.initials: GD
authors.lastname: Nicol
authors.forename: C M
authors.initials: CM
authors.lastname: Hingtgen
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D002211:Capsaicin / Q000494:pharmacology*; D048429:Cell Size; D051379:Mice; D018345:Mice, Knockout; D051839:NFI Transcription Factors / Q000235:genetics / Q000378:metabolism*; D020932:Nerve Growth Factor / Q000494:pharmacology*; D011984:Sensory Receptor Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013045:Species Specificity; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D051839:NFI Transcription Factors; D020932:Nerve Growth Factor; D018631:ras Proteins; D002211:Capsaicin