MOLECULAR LOCALIZATION OF AN ION-BINDING SITE WITHIN THE PORE OF MAMMALIAN SODIUM-CHANNELS

Sodium channels are the major proteins that underlie excitability in nerve, heart, and skeletal muscle. Chemical reaction rate theory was used to analyze the blockage of single wild-type and mutant sodium channels by cadmium ions. The affinity of cadmium for the native tetrodotoxin (TTX)-resistant cardiac channel was much higher than its affinity for the TTX-sensitive skeletal muscle isoform of the channel (mu-l). Mutation of Tyr401 to Cys, the corresponding residue in the cardiac sequence, rendered mu-l highly susceptible to cadmium blockage but resistant to TTX. The binding site was localized approximately 20% of the distance down the electrical field, thus defining the position of a critical residue within the sodium channel pore.