Marked difference in saxitoxin and tetrodotoxin affinity for the human nociceptive voltage-gated sodium channel (Nav1.7) [corrected].
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.
Department of Chemistry, Structural Biology, and Computer Science, Stanford University, Stanford, CA 94305-5080, USA.
James R
JR
Walker
Paul A
PA
Novick
William H
WH
Parsons
Malcolm
M
McGregor
Jeff
J
Zablocki
Vijay S
VS
Pande
J
J
Du Bois
D001224:Aspartic Acid / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D015640:Ion Channel Gating; D008715:Methionine / Q000737:chemistry / Q000378:metabolism; D016296:Mutagenesis; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000737:chemistry / Q000187:drug effects* / Q000502:physiology; D012530:Saxitoxin / Q000633:toxicity*; D013779:Tetrodotoxin / Q000633:toxicity*
D062556:NAV1.7 Voltage-Gated Sodium Channel; C486866:SCN9A protein, human; D001224:Aspartic Acid; D012530:Saxitoxin; D013779:Tetrodotoxin; D008715:Methionine