Interactions between a Pore-Blocking Peptide and the Voltage Sensor of the Sodium Channel: An Electrostatic Approach to Channel Geometry

Few experimental data illuminate the relationship between the molecular structures that mediate ion conduction through voltage-dependent ion channels and the structures responsible for sensing transmembrane voltage and controlling gating. To fill this void, we have used a strongly cationic, mutated mu-conotoxin peptide, which only partially blocks current through voltage-dependent sodium channels, to study voltage-dependent activation gating in both bound and unbound channels. When the peptide binds to the ion-conducting pore, it inhibit channel opening, necessitating stronger depolarization for channel activation. We show that this activation shift could result entirely from electrostatic inhibition of the movement of the voltage-sensing S4 charges and estimate the approximate physical distance through which the S4 charges move.