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

Walker JR, Novick PA, Parsons WH, McGregor M, Zablocki J, Pande VS, Du Bois J.

Proceedings of the National Academy of Sciences, USA (Dec 2012)

Here we use molecular dynamics and chemical informatics methods to better understand sodium channels. This is important as it has applications to developing pain medicines, whose functionality relies on interacting with these channels.

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.