Marked difference in saxitoxin and tetrodotoxin affinity for the human nociceptive voltage-gated sodium channel (Nav1.7) [corrected]

Proc Natl Acad Sci U S A. 2012 Oct 30;109(44):18102-7. doi: 10.1073/pnas.1206952109. Epub 2012 Oct 17.

Abstract

Human nociceptive voltage-gated sodium channel (Na(v)1.7), a target of significant interest for the development of antinociceptive agents, is blocked by low nanomolar concentrations of (-)-tetrodotoxin(TTX) but not (+)-saxitoxin (STX) and (+)-gonyautoxin-III (GTX-III). These findings question the long-accepted view that the 1.7 isoform is both tetrodotoxin- and saxitoxin-sensitive and identify the outer pore region of the channel as a possible target for the design of Na(v)1.7-selective inhibitors. Single- and double-point amino acid mutagenesis studies along with whole-cell electrophysiology recordings establish two domain III residues (T1398 and I1399), which occur as methionine and aspartate in other Na(v) isoforms, as critical determinants of STX and gonyautoxin-III binding affinity. An advanced homology model of the Na(v) pore region is used to provide a structural rationalization for these surprising results.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aspartic Acid / chemistry
  • Aspartic Acid / metabolism
  • Humans
  • Ion Channel Gating*
  • Methionine / chemistry
  • Methionine / metabolism
  • Mutagenesis
  • NAV1.7 Voltage-Gated Sodium Channel / chemistry
  • NAV1.7 Voltage-Gated Sodium Channel / drug effects*
  • NAV1.7 Voltage-Gated Sodium Channel / physiology
  • Saxitoxin / toxicity*
  • Tetrodotoxin / toxicity*

Substances

  • NAV1.7 Voltage-Gated Sodium Channel
  • SCN9A protein, human
  • Aspartic Acid
  • Saxitoxin
  • Tetrodotoxin
  • Methionine