期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 109, 期 44, 页码 18102-18107出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1206952109
关键词
SCN9A; guanidinium toxin
资金
- Stanford Interdisciplinary Graduate Fellowship (SIGF)
- National Institutes of Health [R01-GM062868, R01-NS045684, R21-NS070064]
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.
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