Marked difference in saxitoxin and tetrodoxin affinity for the human nociceptive voltage-gated sodium channel (Na_v 1.7)

摘要

Human nociceptive voltage-gated sodium channel (Na_v 1.7), a target of significant interest for the development of a nti nociceptive agents, is blocked by low nanomolar concentrations of (-)-tetrodotoxin (TTX) but not (+)-saxitoxin (STX) and (+)-gonyautoxin-lll (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_v1.7-selective inhibitors. Single- and double-point amino acid mu-tagenesis studies along with whole-cell electrophysiology recordings establish two domain III residues (T1398 and l1399), which occur as methionine and aspartate in other Na_v isoforms, as critical determinants of STX and gonyautoxin-lll binding affinity. An advanced ho-mology model of the Na_v pore region is used to provide a structural rationalization for these surprising results.