Fig 6.
Gating model for isoflurane inhibition of NaV1.2R involving stabilisation of fast inactivation. (a) Simple Markov gating model of isoflurane inhibition involving primary resting (R), open (O) and fast inactivated (IF) states (R-O-IF model). Transitions between states are indicated by arrows shown with associated rate constants. During activation, channels transition from R to O to IF, and upon repolarization channels recover to availability by transitioning from IF to R. It is assumed that transitions from O to R are negligible and IF is an absorbing state during activation. Curved arrows identify transitions modulated by isoflurane (ISO). Isoflurane enhances (+) transitions from O to IF and slows (−) transitions from IF to R, which together represents IF stabilisation. (b) Simulated responses to single depolarizations (5 ms, 0 mV, Vh= − 70 mV). Normalized probability of state O (P{O}), proportional to current, plotted against time for control (CTL) and isoflurane (ISO). (c) Empirical pulse trains replotted from Fig. 3b and d (Vh= − 70 mV), with pulse durations as indicated. (d) Time course of isoflurane inhibition during a pulse train determined by plotting the fraction of channels inhibited (Fractional Inhibition; 1 − Pulsen/Pulse1) against pulse number. Empirical responses were derived from the pulse trains of panel C shown as blue symbols. Simulated responses are shown as green symbols, Data shown as mean [sd], with pulse durations indicated.