A data-derived model of I_NaP (Model 1). (A) Markov state model optimized to simultaneously fit the experimental data in B–E (see Materials and methods). The closed states C₁–C₄, the open state O₅, and the inactivated states I₆–I₁₀ represent the fast activation and inactivation pathways, whereas the two inactivated states SI₁₁ and SI₁₂ create an alternative, slower inactivation pathway. The k parameters represent voltage-dependent microscopic rate constants, and a and b represent allosteric parameters. All rates are voltage dependent. (B–F) Experimental data (black traces and symbols), as described in Fig. 3 (B–E) and Fig. 2 C (F), and best-fit model predictions (green lines). The traces in C and D were obtained by converting current to conductance, assuming a reversal potential of +35 mV. In D, the initial 20 ms containing the transient were excluded from the fit. The data in F were not part of the fit, and the red waveform represents the prediction of the optimized model. The predicted current drops in amplitude during each action potential in the burst, as caused by the corresponding drop in driving force. In the experimental data, this effect is masked by the much larger I_NaT. Data shown in B and E are mean ± SD.