Augmented sodium currents contribute to the enhanced excitability of small diameter capsaicin-sensitive sensory neurons isolated from Nf1+/⁻ mice.
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.
Wang
Yue
Y
Dept. of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Duan
J-H
JH
Hingtgen
C M
CM
Nicol
G D
GD
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D002211:Capsaicin / Q000494:pharmacology*; D004195:Disease Models, Animal; D006160:Guanosine Triphosphate / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009456:Neurofibromatosis 1 / Q000503:physiopathology; D025542:Neurofibromin 1 / Q000235:genetics* / Q000378:metabolism; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000187:drug effects* / Q000502:physiology*; D018689:Sensory System Agents / Q000494:pharmacology*; D015222:Sodium Channels / Q000502:physiology*; D013779:Tetrodotoxin / Q000494:pharmacology
D025542:Neurofibromin 1; D015221:Potassium Channels; D018689:Sensory System Agents; D015222:Sodium Channels; D013779:Tetrodotoxin; D006160:Guanosine Triphosphate; D016283:Proto-Oncogene Proteins p21(ras); D002211:Capsaicin