Fig 4. E1784K accelerates a component of slow inactivation with 1-10s time constants.

(A1 and A2) Sample inward sodium currents recorded after 20ms to 60s repolarization pulses to -90mV following either a 500ms or 64s depolarization to -30mV. (B) Time course of slow inactivation recovery at -90mV in C373F Na_V1.5 at pH 7.4 following depolarizations to -30mV for durations between 500ms (top curve) and 64s (bottom curve). (B inset) To measure onset and recovery time courses for slow inactivation, cells were depolarized to -10mV (c) following a depolarizing pulse of variable duration to membrane potentials between -30mV and +30mV (a) and a recovery pulse of variable duration to membrane potentials between -120mV and -80mV (b). (C) Time course of slow inactivation onset at -30mV in C373F Na_V1.5 at pH 7.4 with recovery interpulses to -90mV for durations between 100ms (bottom curve) and 10s (top curve). (D) Time constants for the fast component of slow inactivation recovery (-120mV to -80mV) and slow inactivation onset (-30mV and 0mV) plotted versus voltage for C373F and C373F/E1784K Na_V1.5 at pH 7.4 and pH 6.0. The E1784K mutant decelerates the fast component of inactivation recovery at -80mV and accelerates inactivation at 0mV. Decreasing extracellular pH slows the fast component of inactivation onset at 0mV. (E) Time constants for the slow component of slow inactivation recovery (-120mV to -80mV) and slow inactivation onset (-30mV to 30mV) plotted versus voltage for C373F and C373F/E1784K Na_V1.5 at pH 7.4 and pH 6.0. The E1784K mutant accelerates the slow component of recovery at -120mV and -90mV and accelerates the slow component of onset at 0mV. Decreasing extracellular pH slows the slow component of inactivation onset at -30mV, 0mV, and +30mV.