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

Human nociceptive voltage-gated sodium channel (Nav1.7), 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 Nav1.7-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 Nav isoforms, as critical determinants of STX and gonyautoxin-III binding affinity. An advanced homology model of the Nav pore region is used to provide a structural rationalization for these surprising results.