A SINGLE SERINE RESIDUE CONFERS TETRODOTOXIN INSENSITIVITY ON THE RATSENSORY-NEURON-SPECIFIC SODIUM-CHANNEL SNS

Sensory neurons express a sodium channel (SNS) that is highly resistan t to block by tetrodotoxin (IC50 = 60 mu M). SNS is 65% homologous to the cardiac sodium channel, in which a single hydrophilic residue in t he SS2 segment is critical for tetrodotoxin resistance, By site-direct ed mutagenesis, we have substituted phenylalanine for serine at the eq uivalent position in SNS: this mutated (S356E) SNS channel is function ally similar to wild-type SNS when expressed in Xenopus oocytes, but i s potently blocked by tetrodotoxin and saxitoxin with IC(50)s of 2.8 n M and 8.2 nM, respectively, These data provide clues to the rational d esign of selective blockers of SNS with potential as analgesic drugs. (C) 1997 Federation of European Biochemical Societies.