Inactivation pathways of voltage-gated ion channels. Inactivation may occur strictly from the open state (OSI) or pre-open closed states (CSI). A hybrid scenario allowing inactivation from both open and closed states is also likely (OSI + CSI). Gray arrows indicate a subset of this scheme in which interconversion between closed-inactivated and open-inactivated is allowed. For proof-of-principle simulations, the detailed versions of these schemes are shown in Fig. S1.