• James R Walker, Paul A Novick, William H Parsons, Malcolm McGregor, Jeff Zablocki, Vijay S Pande, and J Du Bois.
• Department of Chemistry, Structural Biology, and Computer Science, Stanford University, Stanford, CA 94305-5080, USA.
• Proc. Natl. Acad. Sci. U.S.A. 2012 Oct 30;109(44):18102-7.

AbstractHuman 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.

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