Augmented sodium currents contribute to the enhanced excitability of small diameter capsaicin-sensitive sensory neurons isolated from Nf1+/⁻ mice

J Neurophysiol. 2010 Apr;103(4):2085-94. doi: 10.1152/jn.01010.2009. Epub 2010 Feb 17.

Abstract

Neurofibromin, the product of the Nf1 gene, is a guanosine triphosphatase activating protein (GAP) for p21ras (Ras) that accelerates conversion of active Ras-GTP to inactive Ras-GDP. Sensory neurons with reduced levels of neurofibromin likely have augmented Ras-GTP activity. We reported previously that sensory neurons isolated from a mouse model with a heterozygous mutation of the Nf1 gene (Nf1+/⁻) exhibited greater excitability compared with wild-type mice. To determine the mechanism giving rise to the augmented excitability, differences in specific membrane currents were examined. Consistent with the enhanced excitability of Nf1+/⁻ neurons, peak current densities of both tetrodotoxin-resistant sodium current (TTX-R I(Na)) and TTX-sensitive (TTX-S) I(Na) were significantly larger in Nf1+/⁻ than in wild-type neurons. Although the voltages for half-maximal activation (V(0.5)) were not different, there was a significant depolarizing shift in the V(0.5) for steady-state inactivation of both TTX-R and TTX-S I(Na) in Nf1+/⁻ neurons. In addition, levels of persistent I(Na) were significantly larger in Nf1+/⁻ neurons. Neither delayed rectifier nor A-type potassium currents were altered in Nf1+/⁻ neurons. These results demonstrate that enhanced production of action potentials in Nf1+/⁻ neurons results, in part, from larger current densities and a depolarized voltage dependence of steady-state inactivation for I(Na) that potentially leads to a greater availability of sodium channels at voltages near the firing threshold for the action potential.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Action Potentials / drug effects
  • Action Potentials / physiology
  • Animals
  • Capsaicin / pharmacology*
  • Disease Models, Animal
  • Guanosine Triphosphate / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Neurofibromatosis 1 / physiopathology
  • Neurofibromin 1 / genetics*
  • Neurofibromin 1 / metabolism
  • Potassium Channels / drug effects
  • Potassium Channels / physiology
  • Proto-Oncogene Proteins p21(ras) / metabolism
  • Sensory Receptor Cells / drug effects*
  • Sensory Receptor Cells / physiology*
  • Sensory System Agents / pharmacology*
  • Sodium Channels / physiology*
  • Tetrodotoxin / pharmacology

Substances

  • Neurofibromin 1
  • Potassium Channels
  • Sensory System Agents
  • Sodium Channels
  • Tetrodotoxin
  • Guanosine Triphosphate
  • Proto-Oncogene Proteins p21(ras)
  • Capsaicin