Format

Send to

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

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

Author information

1
Department of Chemistry, Structural Biology, and Computer Science, Stanford University, Stanford, CA 94305-5080, USA.

Erratum in

  • Proc Natl Acad Sci U S A. 2012 Dec 26;109(52):21551.

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.

PMID:
23077250
PMCID:
PMC3497785
DOI:
10.1073/pnas.1206952109
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center