Pharmacological properties of neuronal TTX-resistant sodium channels and the role of a critical serine pore residue

Pflugers Arch. 2005 Dec;451(3):454-63. doi: 10.1007/s00424-005-1463-x. Epub 2005 Jun 25.


Voltage-gated sodium channels can be characterized by their sensitivity to inhibitors. Na(v)1.5 is sensitive to block by cadmium and extracellular QX-314, but relatively insensitive to tetrodotoxin and saxitoxin. Na(v)1.4 is tetrodotoxin- and saxitoxin-sensitive but resistant to cadmium and extracellular QX-314. Na(v)1.8 and Na(v)1.9 generate slowly inactivating (I(TTXr-Slow)) and persistent (I(TTXr-Per)) currents in sensory neurons that are tetrodotoxin-resistant. Tetrodotoxin sensitivity is largely determined by the identity of a single residue; tyrosine 401 in Na(v)1.4, cysteine 374 in Na(v)1.5 and serine 356 and 355 in Na(v)1.8 and Na(v)1.9. We asked whether Na(v)1.8 and Na(v)1.9 share other pharmacological properties as a result of this serine residue. I(TTXr-Slow) and I(TTXr-Per) were saxitoxin-resistant and resistant to internal QX-314. I(TTXr-Slow) was also resistant to external QX-314 and displayed a approximately fourfold higher sensitivity than I(TTXr-Per) to cadmium. The impact of the serine residue was investigated by replacing tyrosine 401 in Na(v)1.4 with serine (Y401S) or cysteine (Y401C). Both mutants were resistant to tetrodotoxin and saxitoxin. Whereas Na(v)1.4-Y401C displayed an increased sensitivity to cadmium and extracellular QX-314, the serine substitution did not alter the sensitivity of Na(v)1.4 to cadmium or QX-314. Our data indicates that while the serine residue determines the sensitivity of I(TTXr-Slow) and I(TTXr-Per) to tetrodotoxin and saxitoxin, it does not determine their insensitivity to QX-314 or their differential sensitivities to cadmium.

MeSH terms

  • Animals
  • Cadmium / pharmacology
  • Cell Line
  • Extracellular Fluid
  • Ganglia, Spinal / physiology
  • Humans
  • Intracellular Fluid
  • Lidocaine / analogs & derivatives
  • Lidocaine / pharmacology
  • Male
  • Neurons, Afferent / physiology
  • Patch-Clamp Techniques
  • Rats
  • Rats, Sprague-Dawley
  • Saxitoxin / pharmacology
  • Serine / physiology*
  • Sodium / metabolism
  • Sodium Channels / chemistry*
  • Sodium Channels / drug effects
  • Tetrodotoxin / pharmacology*


  • Sodium Channels
  • Cadmium
  • QX-314
  • Saxitoxin
  • Tetrodotoxin
  • Serine
  • Lidocaine
  • Sodium