Journal
NEUROSCIENCE LETTERS
Volume 496, Issue 2, Pages 70-74Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.neulet.2011.03.083
Keywords
Dorsal root ganglia; Nerve growth factor; Neurofibromin; Sensitization
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Funding
- National Center for Research Resources, NIH [C06 RR015481-01]
- NIH NINDS [NS46084, NS51668]
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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. (C) 2011 Elsevier Ireland Ltd. All rights reserved.
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